Leukemia, Myelodysplasia, Transplantation

Fish oil capsules

Consuming certain types of fish and taking fish oil supplements may induce chemoresistance, according to research published in JAMA Oncology.

Researchers found that herring and mackerel, as well as 6 different types of fish oil supplements, raised blood levels of the fatty acid 16:4(n-3).

And experiments in mice showed that small amounts of either purified 16:4(n-3) or fish oil induced resistance to the chemotherapy drug cisplatin.

Emile E. Voest, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, and his colleagues conducted this multi-part study.

In one part, the team conducted a survey to determine the rate of fish oil use among patients undergoing cancer treatment (n=118). Thirty-five patients (30%) reported regular use of nutritional supplements, and 13 (11%) said they used supplements containing omega-3 fatty acids.

For another part of the study, the researchers evaluated 6 types of fish oil supplements. All of them contained relevant amounts of 16:4(n-3), ranging from 0.2 µM to 5.7 µM.

The team also recruited healthy volunteers to examine blood levels of 16:4(n-3) after the ingestion of fish oil supplements (n=30) and fish (n=20).

Volunteers had increased blood levels of 16:4(n-3) after the recommended daily amount of 10 mL of fish oil and after a 50 mL dose. Subjects had an almost-complete normalization of blood levels 8 hours after a 10 mL fish oil dose, but they had a more prolonged elevation of fatty acid levels after a 50 mL dose.

Eating 100 grams of herring and mackerel also increased blood levels of 16:4(n-3) compared with tuna, which did not affect blood levels, and salmon,

which resulted in a small, short-lived peak.

Finally, experiments in mice showed that as little as 2.5 pmol of purified 16:4(n-3) or 1 µL of fish oil was sufficient to induce resistance to the chemotherapy drug cisplatin.

The fish oil/cisplatin combination had no significant impact on mouse tumors when compared to vehicle control treatment. The estimated tumor volume difference was 44.1 mm³ (P >0.99).

When the researchers compared cisplatin alone to cisplatin plus 16:4(n-3), the estimated tumor volume difference was 95.5 mm³ (P=0 .04). When they compared vehicle control to cisplatin alone, there was an estimated tumor volume difference of 142.4 mm³ (P=0.001).

The team said these results suggest that simultaneous exposure to chemotherapy and fish oil may be detrimental to cancer patients. So until further data become available, patients should avoid consuming fish oil from the day before chemotherapy until the day after.

Fish oil capsules

Consuming certain types of fish and taking fish oil supplements may induce chemoresistance, according to research published in JAMA Oncology.

Researchers found that herring and mackerel, as well as 6 different types of fish oil supplements, raised blood levels of the fatty acid 16:4(n-3).

And experiments in mice showed that small amounts of either purified 16:4(n-3) or fish oil induced resistance to the chemotherapy drug cisplatin.

Emile E. Voest, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, and his colleagues conducted this multi-part study.

In one part, the team conducted a survey to determine the rate of fish oil use among patients undergoing cancer treatment (n=118). Thirty-five patients (30%) reported regular use of nutritional supplements, and 13 (11%) said they used supplements containing omega-3 fatty acids.

For another part of the study, the researchers evaluated 6 types of fish oil supplements. All of them contained relevant amounts of 16:4(n-3), ranging from 0.2 µM to 5.7 µM.

The team also recruited healthy volunteers to examine blood levels of 16:4(n-3) after the ingestion of fish oil supplements (n=30) and fish (n=20).

Volunteers had increased blood levels of 16:4(n-3) after the recommended daily amount of 10 mL of fish oil and after a 50 mL dose. Subjects had an almost-complete normalization of blood levels 8 hours after a 10 mL fish oil dose, but they had a more prolonged elevation of fatty acid levels after a 50 mL dose.

Eating 100 grams of herring and mackerel also increased blood levels of 16:4(n-3) compared with tuna, which did not affect blood levels, and salmon,

which resulted in a small, short-lived peak.

Finally, experiments in mice showed that as little as 2.5 pmol of purified 16:4(n-3) or 1 µL of fish oil was sufficient to induce resistance to the chemotherapy drug cisplatin.

The fish oil/cisplatin combination had no significant impact on mouse tumors when compared to vehicle control treatment. The estimated tumor volume difference was 44.1 mm³ (P >0.99).

When the researchers compared cisplatin alone to cisplatin plus 16:4(n-3), the estimated tumor volume difference was 95.5 mm³ (P=0 .04). When they compared vehicle control to cisplatin alone, there was an estimated tumor volume difference of 142.4 mm³ (P=0.001).

The team said these results suggest that simultaneous exposure to chemotherapy and fish oil may be detrimental to cancer patients. So until further data become available, patients should avoid consuming fish oil from the day before chemotherapy until the day after.

Fish oil capsules

Consuming certain types of fish and taking fish oil supplements may induce chemoresistance, according to research published in JAMA Oncology.

Researchers found that herring and mackerel, as well as 6 different types of fish oil supplements, raised blood levels of the fatty acid 16:4(n-3).

And experiments in mice showed that small amounts of either purified 16:4(n-3) or fish oil induced resistance to the chemotherapy drug cisplatin.

Emile E. Voest, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, and his colleagues conducted this multi-part study.

In one part, the team conducted a survey to determine the rate of fish oil use among patients undergoing cancer treatment (n=118). Thirty-five patients (30%) reported regular use of nutritional supplements, and 13 (11%) said they used supplements containing omega-3 fatty acids.

For another part of the study, the researchers evaluated 6 types of fish oil supplements. All of them contained relevant amounts of 16:4(n-3), ranging from 0.2 µM to 5.7 µM.

The team also recruited healthy volunteers to examine blood levels of 16:4(n-3) after the ingestion of fish oil supplements (n=30) and fish (n=20).

Volunteers had increased blood levels of 16:4(n-3) after the recommended daily amount of 10 mL of fish oil and after a 50 mL dose. Subjects had an almost-complete normalization of blood levels 8 hours after a 10 mL fish oil dose, but they had a more prolonged elevation of fatty acid levels after a 50 mL dose.

Eating 100 grams of herring and mackerel also increased blood levels of 16:4(n-3) compared with tuna, which did not affect blood levels, and salmon,

which resulted in a small, short-lived peak.

Finally, experiments in mice showed that as little as 2.5 pmol of purified 16:4(n-3) or 1 µL of fish oil was sufficient to induce resistance to the chemotherapy drug cisplatin.

The fish oil/cisplatin combination had no significant impact on mouse tumors when compared to vehicle control treatment. The estimated tumor volume difference was 44.1 mm³ (P >0.99).

When the researchers compared cisplatin alone to cisplatin plus 16:4(n-3), the estimated tumor volume difference was 95.5 mm³ (P=0 .04). When they compared vehicle control to cisplatin alone, there was an estimated tumor volume difference of 142.4 mm³ (P=0.001).

The team said these results suggest that simultaneous exposure to chemotherapy and fish oil may be detrimental to cancer patients. So until further data become available, patients should avoid consuming fish oil from the day before chemotherapy until the day after.

Micrograph showing CML

Image courtesy of UCSD

New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.

They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.

These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.

“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.

“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”

To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.

The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.

TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.

This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.

The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.

“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.

“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”

This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.

Micrograph showing CML

Image courtesy of UCSD

New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.

They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.

These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.

“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.

“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”

To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.

The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.

TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.

This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.

The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.

“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.

“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”

This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.

Micrograph showing CML

Image courtesy of UCSD

New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.

They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.

These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.

“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.

“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”

To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.

The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.

TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.

This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.

The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.

“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.

“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”

This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.

Doctor examining a child

Photo by Logan Tuttle

New research suggests the prevalence of childhood cancer survivors in the US has increased, and the majority of pediatric patients who have survived 5

or more years beyond cancer diagnosis may have at least one chronic health condition.

About 70% of the childhood cancer survivors studied were estimated to have a mild or moderate chronic condition, and nearly a third were estimated to have a severe, disabling, or life-threatening chronic condition.

“Our study findings highlight that a singular focus on curing cancer yields an incomplete picture of childhood cancer survivorship,” said study author Siobhan M. Phillips, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“The burden of chronic conditions in this population is profound, both in occurrence and severity. Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.”

Dr Phillips and her colleagues reported their findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers analyzed data on cancer incidence and survival for children who were diagnosed with cancer between 0 and 19 years of age. The data had been recorded between 1975 and 2011 in 9 different US Surveillance, Epidemiology, and End Results (SEER) registries.

The team also used data from the Childhood Cancer Survivor Study (CCSS) cohort, which had information on a range of potential adverse and late effects of cancer treatment from more than 14,000 long-term survivors of childhood cancers who were treated at 26 cancer centers across the US and Canada.

The investigators first obtained estimates of the probability of each measure of morbidity from CCSS and then multiplied these estimates by the relevant number of survivors in the US estimated from the SEER data.

The researchers estimated the number of childhood cancer survivors in the US to be 388,501, which is an increase of 59,849 from the previous estimate made in 2005 by a team from the National Cancer Institute.

Of these patients, about 84% had survived 5 or more years post-diagnosis, and about 45% had survived for 20 years or more.

About 70% of the survivors were estimated to have a mild or moderate chronic condition (grade 1-2), and about 32% were estimated to have a severe, disabling, or life-threatening chronic condition (grade 3-4).

An estimated 35% of the survivors, ages 20 to 49, had neurocognitive dysfunction. About 13% to 17% of survivors in this age group had self-reported functional impairment, activity limitations, impaired mental health, pain, or anxiety/fear.

“We know that many of these morbidities are at least somewhat modifiable in the general population,” Dr Phillips noted. “However, we don’t know if typical population guidelines for preventive behaviors apply to [childhood cancer survivors].”

“We need to develop a better understanding of the multilevel factors—including, but not limited to, physical activity, diet, and treatment characteristics—which influence childhood cancer survivors’ susceptibility to these morbidities in order to effectively prevent and delay their onset.”

Doctor examining a child

Photo by Logan Tuttle

New research suggests the prevalence of childhood cancer survivors in the US has increased, and the majority of pediatric patients who have survived 5

or more years beyond cancer diagnosis may have at least one chronic health condition.

About 70% of the childhood cancer survivors studied were estimated to have a mild or moderate chronic condition, and nearly a third were estimated to have a severe, disabling, or life-threatening chronic condition.

“Our study findings highlight that a singular focus on curing cancer yields an incomplete picture of childhood cancer survivorship,” said study author Siobhan M. Phillips, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“The burden of chronic conditions in this population is profound, both in occurrence and severity. Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.”

Dr Phillips and her colleagues reported their findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers analyzed data on cancer incidence and survival for children who were diagnosed with cancer between 0 and 19 years of age. The data had been recorded between 1975 and 2011 in 9 different US Surveillance, Epidemiology, and End Results (SEER) registries.

The team also used data from the Childhood Cancer Survivor Study (CCSS) cohort, which had information on a range of potential adverse and late effects of cancer treatment from more than 14,000 long-term survivors of childhood cancers who were treated at 26 cancer centers across the US and Canada.

The investigators first obtained estimates of the probability of each measure of morbidity from CCSS and then multiplied these estimates by the relevant number of survivors in the US estimated from the SEER data.

The researchers estimated the number of childhood cancer survivors in the US to be 388,501, which is an increase of 59,849 from the previous estimate made in 2005 by a team from the National Cancer Institute.

Of these patients, about 84% had survived 5 or more years post-diagnosis, and about 45% had survived for 20 years or more.

About 70% of the survivors were estimated to have a mild or moderate chronic condition (grade 1-2), and about 32% were estimated to have a severe, disabling, or life-threatening chronic condition (grade 3-4).

An estimated 35% of the survivors, ages 20 to 49, had neurocognitive dysfunction. About 13% to 17% of survivors in this age group had self-reported functional impairment, activity limitations, impaired mental health, pain, or anxiety/fear.

“We know that many of these morbidities are at least somewhat modifiable in the general population,” Dr Phillips noted. “However, we don’t know if typical population guidelines for preventive behaviors apply to [childhood cancer survivors].”

“We need to develop a better understanding of the multilevel factors—including, but not limited to, physical activity, diet, and treatment characteristics—which influence childhood cancer survivors’ susceptibility to these morbidities in order to effectively prevent and delay their onset.”

Doctor examining a child

Photo by Logan Tuttle

New research suggests the prevalence of childhood cancer survivors in the US has increased, and the majority of pediatric patients who have survived 5

or more years beyond cancer diagnosis may have at least one chronic health condition.

About 70% of the childhood cancer survivors studied were estimated to have a mild or moderate chronic condition, and nearly a third were estimated to have a severe, disabling, or life-threatening chronic condition.

“Our study findings highlight that a singular focus on curing cancer yields an incomplete picture of childhood cancer survivorship,” said study author Siobhan M. Phillips, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“The burden of chronic conditions in this population is profound, both in occurrence and severity. Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.”

Dr Phillips and her colleagues reported their findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers analyzed data on cancer incidence and survival for children who were diagnosed with cancer between 0 and 19 years of age. The data had been recorded between 1975 and 2011 in 9 different US Surveillance, Epidemiology, and End Results (SEER) registries.

The team also used data from the Childhood Cancer Survivor Study (CCSS) cohort, which had information on a range of potential adverse and late effects of cancer treatment from more than 14,000 long-term survivors of childhood cancers who were treated at 26 cancer centers across the US and Canada.

The investigators first obtained estimates of the probability of each measure of morbidity from CCSS and then multiplied these estimates by the relevant number of survivors in the US estimated from the SEER data.

The researchers estimated the number of childhood cancer survivors in the US to be 388,501, which is an increase of 59,849 from the previous estimate made in 2005 by a team from the National Cancer Institute.

Of these patients, about 84% had survived 5 or more years post-diagnosis, and about 45% had survived for 20 years or more.

About 70% of the survivors were estimated to have a mild or moderate chronic condition (grade 1-2), and about 32% were estimated to have a severe, disabling, or life-threatening chronic condition (grade 3-4).

An estimated 35% of the survivors, ages 20 to 49, had neurocognitive dysfunction. About 13% to 17% of survivors in this age group had self-reported functional impairment, activity limitations, impaired mental health, pain, or anxiety/fear.

“We know that many of these morbidities are at least somewhat modifiable in the general population,” Dr Phillips noted. “However, we don’t know if typical population guidelines for preventive behaviors apply to [childhood cancer survivors].”

“We need to develop a better understanding of the multilevel factors—including, but not limited to, physical activity, diet, and treatment characteristics—which influence childhood cancer survivors’ susceptibility to these morbidities in order to effectively prevent and delay their onset.”

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Tomasz Cierpicki, PhD,

and Jolanta Grembecka, PhD

Photo courtesy of the

University of Michigan

Two small-molecule inhibitors can fight aggressive, acute leukemias by targeting a protein-protein interaction, according to preclinical research published in Cancer Cell.

The compounds, MI-463 and MI-503, work by inhibiting the interaction between menin and mixed-lineage leukemia (MLL) fusion proteins.

Menin binds to the N-terminal fragment of MLL retained in all MLL fusion proteins, and the fusion proteins require menin for leukemogenic activity.

That’s why Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, both of the University of Michigan in Ann Arbor, have been working for several years to identify small-molecule inhibitors that would block the MLL-menin interaction.

“The MLL-menin interaction is a good drug target because it’s the primary driver in [MLL] leukemia,” Dr Grembecka said. “By blocking this interaction, it’s very likely to stop the cancer.”

With that in mind, Dr Grembecka and her colleagues tested 2 compounds they developed, MI-463 and MI-503, in cell lines and mice with MLL leukemia. The compounds blocked the MLL-menin interaction without affecting normal hematopoiesis.

The team also noted that both compounds demonstrated metabolic stability and favorable pharmacokinetic profiles.

“Against all odds, we decided to explore finding a way to block the MLL-menin interaction with small molecules,” Dr Cierpicki said. “From nothing, we have been able to identify and greatly improve a compound and show that it’s got valuable potential in blocking MLL fusion leukemia in animal models.”

In a separate study published in Nature Medicine, the researchers discovered that menin and MLL play a role in androgen receptor signaling, a key driver of prostate cancer.

The team found that MI-503 and MI-136, another inhibitor of the menin-MLL interaction, were both active against castration-resistant prostate cancer in vitro and in vivo.

The researchers said they will continue to investigate the role of MLL in castration-resistant prostate cancer. And they plan to further refine their inhibitors and put the compounds through more advanced preclinical testing in MLL leukemia.

Tomasz Cierpicki, PhD,

and Jolanta Grembecka, PhD

Photo courtesy of the

University of Michigan

Two small-molecule inhibitors can fight aggressive, acute leukemias by targeting a protein-protein interaction, according to preclinical research published in Cancer Cell.

The compounds, MI-463 and MI-503, work by inhibiting the interaction between menin and mixed-lineage leukemia (MLL) fusion proteins.

Menin binds to the N-terminal fragment of MLL retained in all MLL fusion proteins, and the fusion proteins require menin for leukemogenic activity.

That’s why Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, both of the University of Michigan in Ann Arbor, have been working for several years to identify small-molecule inhibitors that would block the MLL-menin interaction.

“The MLL-menin interaction is a good drug target because it’s the primary driver in [MLL] leukemia,” Dr Grembecka said. “By blocking this interaction, it’s very likely to stop the cancer.”

With that in mind, Dr Grembecka and her colleagues tested 2 compounds they developed, MI-463 and MI-503, in cell lines and mice with MLL leukemia. The compounds blocked the MLL-menin interaction without affecting normal hematopoiesis.

The team also noted that both compounds demonstrated metabolic stability and favorable pharmacokinetic profiles.

“Against all odds, we decided to explore finding a way to block the MLL-menin interaction with small molecules,” Dr Cierpicki said. “From nothing, we have been able to identify and greatly improve a compound and show that it’s got valuable potential in blocking MLL fusion leukemia in animal models.”

In a separate study published in Nature Medicine, the researchers discovered that menin and MLL play a role in androgen receptor signaling, a key driver of prostate cancer.

The team found that MI-503 and MI-136, another inhibitor of the menin-MLL interaction, were both active against castration-resistant prostate cancer in vitro and in vivo.

The researchers said they will continue to investigate the role of MLL in castration-resistant prostate cancer. And they plan to further refine their inhibitors and put the compounds through more advanced preclinical testing in MLL leukemia.

Tomasz Cierpicki, PhD,

and Jolanta Grembecka, PhD

Photo courtesy of the

University of Michigan

Two small-molecule inhibitors can fight aggressive, acute leukemias by targeting a protein-protein interaction, according to preclinical research published in Cancer Cell.

The compounds, MI-463 and MI-503, work by inhibiting the interaction between menin and mixed-lineage leukemia (MLL) fusion proteins.

Menin binds to the N-terminal fragment of MLL retained in all MLL fusion proteins, and the fusion proteins require menin for leukemogenic activity.

That’s why Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, both of the University of Michigan in Ann Arbor, have been working for several years to identify small-molecule inhibitors that would block the MLL-menin interaction.

“The MLL-menin interaction is a good drug target because it’s the primary driver in [MLL] leukemia,” Dr Grembecka said. “By blocking this interaction, it’s very likely to stop the cancer.”

With that in mind, Dr Grembecka and her colleagues tested 2 compounds they developed, MI-463 and MI-503, in cell lines and mice with MLL leukemia. The compounds blocked the MLL-menin interaction without affecting normal hematopoiesis.

The team also noted that both compounds demonstrated metabolic stability and favorable pharmacokinetic profiles.

“Against all odds, we decided to explore finding a way to block the MLL-menin interaction with small molecules,” Dr Cierpicki said. “From nothing, we have been able to identify and greatly improve a compound and show that it’s got valuable potential in blocking MLL fusion leukemia in animal models.”

In a separate study published in Nature Medicine, the researchers discovered that menin and MLL play a role in androgen receptor signaling, a key driver of prostate cancer.

The team found that MI-503 and MI-136, another inhibitor of the menin-MLL interaction, were both active against castration-resistant prostate cancer in vitro and in vivo.

The researchers said they will continue to investigate the role of MLL in castration-resistant prostate cancer. And they plan to further refine their inhibitors and put the compounds through more advanced preclinical testing in MLL leukemia.

Fatih Uckun, MD, PhD

Photo courtesy of Dr Uckun

An engineered protein can enhance the effects of radiation and even overcome radiation resistance to treat B-precursor acute lymphoblastic leukemia (ALL), according to research published in EBioMedicine.

The protein, CD19L-sTRAIL, is a fusion of the CD19 ligand protein, which seeks out and binds to leukemia cells, with soluble TRAIL, a protein that can amplify the potency of radiation if it can be anchored on the membrane of leukemia cells.

Researchers found that CD19L-sTRAIL augmented the potency of radiation therapy even against the most aggressive and radiation-resistant forms of leukemia.

“Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with [CD19L-sTRAIL],” said Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles in California.

“Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice.”

The researchers found that a combination of low-dose total body irradiation (TBI) and CD19L-sTRAIL greatly improved event-free survival (EFS) in mice that had received a typically fatal dose of cells from a patient with relapsed B-precursor ALL.

The median EFS for mice treated with CD19L-sTRAIL plus low-dose TBI was 72 days, which was significantly longer than the EFS for untreated control mice (17 days, P<0.0001), mice that received TBI alone (64 days, P=0.0014), mice that received CD19L-sTRAIL alone (20 days, P=0.0022), and mice that received a combination of vincristine, dexamethasone, and PEG-asparaginase (17 days, P=0.0033).

Dr Uckun and his colleagues noted that none of the mice that received CD19L-sTRAIL and TBI experienced a toxic death or signs of treatment-related toxicity.

The team also found that TBI plus CD19L-sTRAIL improved progression-free survival (PFS) in CD22ΔE12xBCR-ABL double transgenic mice with radiation-resistant, advanced stage, CD19+ murine B-precursor ALL with lymphomatous features.

The mean PFS was 24.0 ± 4.0 days for mice that received CD19L-sTRAIL plus TBI, which was significantly longer than the PFS for control mice (0 ± 0 days, P<0.0001), mice that received CD19L-sTRAIL alone (3.4 ± 0.9 days, P=0.0003), and mice that received TBI alone (9.0 ± 4.6 days, P=0.020).

Based on these results, Dr Uckun and his colleagues believe that incorporating CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk B-precursor ALL could improve survival after hematopoietic stem cell transplant.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Fatih Uckun, MD, PhD

Photo courtesy of Dr Uckun

An engineered protein can enhance the effects of radiation and even overcome radiation resistance to treat B-precursor acute lymphoblastic leukemia (ALL), according to research published in EBioMedicine.

The protein, CD19L-sTRAIL, is a fusion of the CD19 ligand protein, which seeks out and binds to leukemia cells, with soluble TRAIL, a protein that can amplify the potency of radiation if it can be anchored on the membrane of leukemia cells.

Researchers found that CD19L-sTRAIL augmented the potency of radiation therapy even against the most aggressive and radiation-resistant forms of leukemia.

“Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with [CD19L-sTRAIL],” said Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles in California.

“Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice.”

The researchers found that a combination of low-dose total body irradiation (TBI) and CD19L-sTRAIL greatly improved event-free survival (EFS) in mice that had received a typically fatal dose of cells from a patient with relapsed B-precursor ALL.

The median EFS for mice treated with CD19L-sTRAIL plus low-dose TBI was 72 days, which was significantly longer than the EFS for untreated control mice (17 days, P<0.0001), mice that received TBI alone (64 days, P=0.0014), mice that received CD19L-sTRAIL alone (20 days, P=0.0022), and mice that received a combination of vincristine, dexamethasone, and PEG-asparaginase (17 days, P=0.0033).

Dr Uckun and his colleagues noted that none of the mice that received CD19L-sTRAIL and TBI experienced a toxic death or signs of treatment-related toxicity.

The team also found that TBI plus CD19L-sTRAIL improved progression-free survival (PFS) in CD22ΔE12xBCR-ABL double transgenic mice with radiation-resistant, advanced stage, CD19+ murine B-precursor ALL with lymphomatous features.

The mean PFS was 24.0 ± 4.0 days for mice that received CD19L-sTRAIL plus TBI, which was significantly longer than the PFS for control mice (0 ± 0 days, P<0.0001), mice that received CD19L-sTRAIL alone (3.4 ± 0.9 days, P=0.0003), and mice that received TBI alone (9.0 ± 4.6 days, P=0.020).

Based on these results, Dr Uckun and his colleagues believe that incorporating CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk B-precursor ALL could improve survival after hematopoietic stem cell transplant.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Fatih Uckun, MD, PhD

Photo courtesy of Dr Uckun

An engineered protein can enhance the effects of radiation and even overcome radiation resistance to treat B-precursor acute lymphoblastic leukemia (ALL), according to research published in EBioMedicine.

The protein, CD19L-sTRAIL, is a fusion of the CD19 ligand protein, which seeks out and binds to leukemia cells, with soluble TRAIL, a protein that can amplify the potency of radiation if it can be anchored on the membrane of leukemia cells.

Researchers found that CD19L-sTRAIL augmented the potency of radiation therapy even against the most aggressive and radiation-resistant forms of leukemia.

“Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with [CD19L-sTRAIL],” said Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles in California.

“Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice.”

The researchers found that a combination of low-dose total body irradiation (TBI) and CD19L-sTRAIL greatly improved event-free survival (EFS) in mice that had received a typically fatal dose of cells from a patient with relapsed B-precursor ALL.

The median EFS for mice treated with CD19L-sTRAIL plus low-dose TBI was 72 days, which was significantly longer than the EFS for untreated control mice (17 days, P<0.0001), mice that received TBI alone (64 days, P=0.0014), mice that received CD19L-sTRAIL alone (20 days, P=0.0022), and mice that received a combination of vincristine, dexamethasone, and PEG-asparaginase (17 days, P=0.0033).

Dr Uckun and his colleagues noted that none of the mice that received CD19L-sTRAIL and TBI experienced a toxic death or signs of treatment-related toxicity.

The team also found that TBI plus CD19L-sTRAIL improved progression-free survival (PFS) in CD22ΔE12xBCR-ABL double transgenic mice with radiation-resistant, advanced stage, CD19+ murine B-precursor ALL with lymphomatous features.

The mean PFS was 24.0 ± 4.0 days for mice that received CD19L-sTRAIL plus TBI, which was significantly longer than the PFS for control mice (0 ± 0 days, P<0.0001), mice that received CD19L-sTRAIL alone (3.4 ± 0.9 days, P=0.0003), and mice that received TBI alone (9.0 ± 4.6 days, P=0.020).

Based on these results, Dr Uckun and his colleagues believe that incorporating CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk B-precursor ALL could improve survival after hematopoietic stem cell transplant.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Lab mice

Photo by Aaron Logan

Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.

The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.

So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.

Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.

When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.

Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.

So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.

They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.

Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.

The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.

Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.

“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.

“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”

Lab mice

Photo by Aaron Logan

Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.

The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.

So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.

Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.

When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.

Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.

So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.

They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.

Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.

The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.

Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.

“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.

“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”

Lab mice

Photo by Aaron Logan

Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.

The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.

So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.

Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.

When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.

Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.

So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.

They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.

Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.

The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.

Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.

“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.

“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”

Lab mouse

In developing a compound that exhibits activity against a type of acute myeloid leukemia (AML), investigators have shown that transcription factors are, in fact, “druggable.”

The compound, AI-10-49, selectively binds to the mutated transcription factor CBFβ-SMMHC, and this prevents CBFβ-SMMHC from binding to another transcription factor, RUNX1.

In this way, AI-10-49 restores RUNX1 transcriptional activity, which leads to the death of inv(16) AML cells in vitro and in vivo.

“This drug that we’ve developed is . . . targeting a class of proteins that hasn’t been targeted for drug development very much in the past,” said study author John H. Bushweller, PhD, of the University of Virginia Health System in Charlottesville.

“It’s really a new paradigm, a new approach to try to treat these diseases. This class of proteins is very important for determining how much of many other proteins are made, so it’s a unique way of changing the way the cell behaves.”

Dr Bushweller and his colleagues described their work in Science.

The investigators noted that CBFβ-SMMHC is expressed in AML with the chromosome inversion inv(16)(p13q22). And CBFβ-SMMHC outcompetes wild-type CBFβ for binding to RUNX1, thereby deregulating RUNX1 activity in hematopoiesis and inducing AML.

“When you target a mutated protein in a cancer, you would ideally like to inhibit that mutated form of the protein but not affect the normal form of the protein that’s still there,” Dr Bushweller said. “In the case of [AI-10-49], we’ve achieved that.”

He and his colleagues tested AI-10-49 in 11 leukemia cells lines and found that only ME-1 cells were highly sensitive to the treatment. AI-10-49 effectively dissociated RUNX1 from CBFβ-SMMHC in ME-1 cells, with 90% dissociation after 6 hours of treatment.

But the drug had a modest effect on CBFβ-RUNX1 association. It also had negligible activity in normal human bone marrow cells.

The investigators then tested AI-10-49 in a mouse model of inv(16) AML. Control mice (vehicle-treated) succumbed to leukemia in a median of 33.5 days, compared to a median of 61 days for mice that received AI-10-49.

Dr Bushweller and his colleagues did not evaluate toxicity after long-term exposure to AI-10-49, but they found no evidence of toxicity after 7 days of AI-10-49 treatment.

Next, the investigators tested AI-10-49 in 4 primary inv(16) AML cell samples. They saw a reduction in leukemia cell viability when AI-10-49 was administered at 5 μM and 10 μM concentrations. Bivalent AI-10-49 was more potent than monovalent AI-10-47.

The team said these results suggest that direct inhibition of CBFβ-SMMHC may be an effective therapeutic approach for inv(16) AML, and the findings provide support for therapies targeting transcription factors.

Lab mouse

In developing a compound that exhibits activity against a type of acute myeloid leukemia (AML), investigators have shown that transcription factors are, in fact, “druggable.”

The compound, AI-10-49, selectively binds to the mutated transcription factor CBFβ-SMMHC, and this prevents CBFβ-SMMHC from binding to another transcription factor, RUNX1.

In this way, AI-10-49 restores RUNX1 transcriptional activity, which leads to the death of inv(16) AML cells in vitro and in vivo.

“This drug that we’ve developed is . . . targeting a class of proteins that hasn’t been targeted for drug development very much in the past,” said study author John H. Bushweller, PhD, of the University of Virginia Health System in Charlottesville.

“It’s really a new paradigm, a new approach to try to treat these diseases. This class of proteins is very important for determining how much of many other proteins are made, so it’s a unique way of changing the way the cell behaves.”

Dr Bushweller and his colleagues described their work in Science.

The investigators noted that CBFβ-SMMHC is expressed in AML with the chromosome inversion inv(16)(p13q22). And CBFβ-SMMHC outcompetes wild-type CBFβ for binding to RUNX1, thereby deregulating RUNX1 activity in hematopoiesis and inducing AML.

“When you target a mutated protein in a cancer, you would ideally like to inhibit that mutated form of the protein but not affect the normal form of the protein that’s still there,” Dr Bushweller said. “In the case of [AI-10-49], we’ve achieved that.”

He and his colleagues tested AI-10-49 in 11 leukemia cells lines and found that only ME-1 cells were highly sensitive to the treatment. AI-10-49 effectively dissociated RUNX1 from CBFβ-SMMHC in ME-1 cells, with 90% dissociation after 6 hours of treatment.

But the drug had a modest effect on CBFβ-RUNX1 association. It also had negligible activity in normal human bone marrow cells.

The investigators then tested AI-10-49 in a mouse model of inv(16) AML. Control mice (vehicle-treated) succumbed to leukemia in a median of 33.5 days, compared to a median of 61 days for mice that received AI-10-49.

Dr Bushweller and his colleagues did not evaluate toxicity after long-term exposure to AI-10-49, but they found no evidence of toxicity after 7 days of AI-10-49 treatment.

Next, the investigators tested AI-10-49 in 4 primary inv(16) AML cell samples. They saw a reduction in leukemia cell viability when AI-10-49 was administered at 5 μM and 10 μM concentrations. Bivalent AI-10-49 was more potent than monovalent AI-10-47.

The team said these results suggest that direct inhibition of CBFβ-SMMHC may be an effective therapeutic approach for inv(16) AML, and the findings provide support for therapies targeting transcription factors.

Lab mouse

In developing a compound that exhibits activity against a type of acute myeloid leukemia (AML), investigators have shown that transcription factors are, in fact, “druggable.”

The compound, AI-10-49, selectively binds to the mutated transcription factor CBFβ-SMMHC, and this prevents CBFβ-SMMHC from binding to another transcription factor, RUNX1.

In this way, AI-10-49 restores RUNX1 transcriptional activity, which leads to the death of inv(16) AML cells in vitro and in vivo.

“This drug that we’ve developed is . . . targeting a class of proteins that hasn’t been targeted for drug development very much in the past,” said study author John H. Bushweller, PhD, of the University of Virginia Health System in Charlottesville.

“It’s really a new paradigm, a new approach to try to treat these diseases. This class of proteins is very important for determining how much of many other proteins are made, so it’s a unique way of changing the way the cell behaves.”

Dr Bushweller and his colleagues described their work in Science.

The investigators noted that CBFβ-SMMHC is expressed in AML with the chromosome inversion inv(16)(p13q22). And CBFβ-SMMHC outcompetes wild-type CBFβ for binding to RUNX1, thereby deregulating RUNX1 activity in hematopoiesis and inducing AML.

“When you target a mutated protein in a cancer, you would ideally like to inhibit that mutated form of the protein but not affect the normal form of the protein that’s still there,” Dr Bushweller said. “In the case of [AI-10-49], we’ve achieved that.”

He and his colleagues tested AI-10-49 in 11 leukemia cells lines and found that only ME-1 cells were highly sensitive to the treatment. AI-10-49 effectively dissociated RUNX1 from CBFβ-SMMHC in ME-1 cells, with 90% dissociation after 6 hours of treatment.

But the drug had a modest effect on CBFβ-RUNX1 association. It also had negligible activity in normal human bone marrow cells.

The investigators then tested AI-10-49 in a mouse model of inv(16) AML. Control mice (vehicle-treated) succumbed to leukemia in a median of 33.5 days, compared to a median of 61 days for mice that received AI-10-49.

Dr Bushweller and his colleagues did not evaluate toxicity after long-term exposure to AI-10-49, but they found no evidence of toxicity after 7 days of AI-10-49 treatment.

Next, the investigators tested AI-10-49 in 4 primary inv(16) AML cell samples. They saw a reduction in leukemia cell viability when AI-10-49 was administered at 5 μM and 10 μM concentrations. Bivalent AI-10-49 was more potent than monovalent AI-10-47.

The team said these results suggest that direct inhibition of CBFβ-SMMHC may be an effective therapeutic approach for inv(16) AML, and the findings provide support for therapies targeting transcription factors.

Drug production

Photo courtesy of the US FDA

The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ponatinib is also approved to treat patients with Ph⁺ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.

Trial results

The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph⁺ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph⁺ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph⁺ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety issues

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.

Drug production

Photo courtesy of the US FDA

The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ponatinib is also approved to treat patients with Ph⁺ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.

Trial results

The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph⁺ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph⁺ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph⁺ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety issues

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.

Drug production

Photo courtesy of the US FDA

The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ponatinib is also approved to treat patients with Ph⁺ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.

Trial results

The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph⁺ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph⁺ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph⁺ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety issues

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.