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AACR Conference Highlights Promising Early Research on Blood Malignancies

Samson, Kurt

doi: 10.1097/01.COT.0000456297.02980.39
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At the American Association for Cancer Research's first conference devoted specifically to research on hematologic cancers, investigators presented promising early findings addressing issues such as overcoming resistance to existing chemotherapy drugs and an investigational small molecule drug that prolonged survival in mouse models of acute myeloid leukemia (AML) and refractory multiple myeloma by blocking the protein RNA polymerase.

The meeting, titled “Hematologic Malignancies: Translating Discoveries into Novel Therapies,” was held September 20-23 in Philadelphia.

“By bringing together investigators across different blood cancers and themes, we are presenting clearly cutting-edge science, in hopes of bringing new therapies from bench to bedside,” said Kenneth C. Anderson, MD, the moderator of a teleconference for reporters that highlights some of the especially promising findings. He is Kraft Family Professor of Medicine at Harvard Medical School and Director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

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CX-5461 Blocks RNA Polymerase I, Prolonging Survival in AML & Myeloma Mouse Models

Ross D. Hannan, PhD, Head of the Oncogenic Signaling and Growth Control Program and Professor at the Peter MacCallum Cancer Center in Australia, reported that the investigational drug CX-5461, which blocks RNA polymerase I (Pol I), prolonged survival in mouse models of acute myeloid leukemia (AML) and refractory multiple myeloma (MM), regardless of P53 status.

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He and his colleagues focused on Pol I, he explained, because it is consistently upregulated in cancers, especially hematologic malignancies, as well as in normal cells.

In a Phase I study, CX-5461 was found to significantly extend overall survival in mice with a highly aggressive form of AML, the MLL/ENL + Nras model. Median survival for untreated animals was 17 days, compared with 21 days for mice treated with standard chemotherapy of cytarabine and doxorubicin, but 36 days for those administered CX-5461.

Moreover, in mice with aggressive V-kappa-MYC multiple myeloma, median survival was 103.5 days in untreated mice versus 175 days with those treated with CX-5461.

“We were excited that therapeutic doses of CX-5461 had little effect on normal cells,” Hannan said. “Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called housekeeping protein that is essential to all cells for survival.”

A clinical trial is now ongoing, he said, and the team is currently testing dose-escalation parameters. He said that because inhibition of Pol I is involved in a large number of other large tumors, he MD of it not as potential personalized therapy, but as “impersonalized treatment.”

Commenting on the findings, Anderson said the study is exciting, because it appears to work, even in p53-deleted cancers where solid tumors and hematologic malignancies are largely untreatable. He also wondered if it might be possible to move forward in screening eligible patients for a future clinical trial.

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Drug Resistance

Douglas Lauffenburger, PhD, Professor and Head of the Biological Engineering Department at the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, reported new research on overcoming drug resistance by treating blood cancers in advance, using a combination of drugs based on the vulnerabilities of individual tumors.

“Our goal is to identify vulnerabilities across different stages of tumor evolution while it is developing resistance to initial treatment, to help guide drug combination strategies,” he said.

“There may be many stages in a tumor evolution while under treatment that may make them vulnerable to already existing therapies. Rather than waiting for the tumor to become resistant to the first treatment and then thinking about a second-line drug to use, we can capitalize on opportunities that exploit vulnerabilities at different early stages as the tumor is evolving to become resistant to the first drug.”

He described an initial screening study using a combination of computational and experimental approaches in mouse acute lymphoblastic leukemia (ALL) cells as the cells evolved, and assessing which drugs might be effective against certain human chronic myelogenous leukemia (CML) cell lines as they develop.

The next step is developing combinations that might treat evolving tumors in humans, he said.

Lauffenburger and his co-investigators used escalating doses of imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells and, as some cells developed resistance to a particular drug, they treated the resistant cells with other drugs to check for cross-resistance. They found that resistant cells surviving at low multiples of the original drug dose actually demonstrated sensitization to certain other drugs with the sensitization eliminated with higher doses.

“Instead of looking only for the most resistant population of ALL cells at the end of this selection process, we monitored drug sensitivity of cells at each stage of the dose escalation,” Lauffenburger explained. “This led us to discover the vulnerabilities of a tumor at different stages of clonal evolution, a phenomenon we would have missed if we only analyzed for drug sensitivity at the last stage of this process, which is equivalent to when a patient has relapsed.”

The team has recently published two papers on ascertaining the most appropriate combinations—one in Proceedings of the National Academy of Sciences (2014;111:10773-10778) and the other in Cancer Discovery (2014;4:166-174).

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Tyrosine Kinase Inhibition in ALL

Tyrosine kinase inhibitors may improve treatment outcomes for children and young adults with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), which has a very poor prognosis, according to a presentation by Kathryn Roberts, PhD, a postdoctoral research associate in pathology at St. Jude Children's Research Hospital.

She and her colleagues recently described a subtype of B-cell acute lymphoblastic leukemia characterized by genetic alterations involving tyrosine kinases. They wanted to investigate whether these alterations might also contribute to the development of Ph-like ALL, and whether it too could be targeted with TKIs.

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“We showed for the first time that the kinase alterations we tested contribute to the development of Ph-like ALL, and that Ph-like ALL can be treated effectively with tyrosine kinase inhibitors in animal models,” she said. “These findings provide a strong rationale for treating Ph-like ALL patients with targeted therapies to improve their survival.”

She explained that the team used a new strain of mice they developed, the first experimental model of Ph-induced ALL. “Our studies show that different FDA-approved TKIs such as imatinib, dasatinib, ruxolitinib, or crizotinib could potentially be used to treat Ph-like ALL patients, depending on the type of kinase alterations of their tumors.”

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Bacterial Toxin Therapy

Erin K. Willert, PhD, Executive Vice President of Research and Development at Molecular Templates Inc. in Georgetown, Texas, described an investigational, bacterial toxin-based therapy that targets the CD38 protein, which is found on the surface of many human blood cancer cells, including multiple myeloma.

In mice with human tumor cells the treatment dramatically increased survival, she reported. “Although there are treatment options for patients with multiple myeloma, there is currently no cure, and many patients receive multiple treatments to manage the disease.”

In the study, the researchers found that the growth of human cancer cells in the mice was substantially decreased, and, in some cases even eliminated, following treatment with the investigational CD38-targeted therapy.

“Our results give us confidence in moving the drug forward toward clinical trials for CD38-positive B-cell malignancies such as multiple myeloma. Moreover, since our CD38-targeted engineered toxin body works differently than current therapeutics, we think that our investigational therapy has the opportunity to be effective in cases of relapsed or refractory multiple myeloma and other CD38-positive B-cell malignancies.”

The researchers used a CD38-targeted toxin body specially engineered to recognize the CD38 protein on the surface of a cancer cell and deliver a modified bacterial toxin that enters the cancer cell, then shuts down protein production, and kills the cell.

“We believe the concentrations of the investigational CD38-targeted engineered toxin body in the mice will be relevant to the doses used in humans; however, more preclinical studies are needed before we can test the therapy in the clinic,” she said.

Anderson cautioned, however, that CD38 affects immunity in all cells, not just tumors. “The key is to find a therapeutic window,” although the research is still at the stage of moving into clinical trials.

© 2014 by Lippincott Williams & Wilkins, Inc.
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