Solving the problem of drug-resistant cancer

To discover ways to prevent or delay resistance to cancer therapies, a new NCI-funded center at OHSU is exploring how acute myeloid leukemia cells evolve and adapt.

The first successful targeted cancer therapies seemed to portend a future in which all tumors might be stopped by deploying precisely designed drugs to cancel the molecular signals driving their growth.

Alas, it wasn’t so easy. Most types of cancer have proven capable of evolving resistance to targeted therapies. The treatment may dramatically shrink tumors, but resistant cancer cells can survive, and within months tumors resume their fatal progression.

In an attempt to solve the resistance problem, the OHSU Knight Cancer Institute and a select group of other cancer research centers are forming a major new consortium backed by the National Cancer Institute. Together, the five Drug Resistance and Sensitivity Centers are aiming to dig deeply into the ways that cancer cells evolve and adapt, and find strategies to prevent or delay resistance.

“We have some really compelling data supporting new approaches,” said Shannon McWeeney, Ph.D., a professor and head of the Division of Bioinformatics and Computational Biology in the Department of Medical Informatics and Clinical Epidemiology  in the OHSU School of Medicine. She’s one of the principle investigators for the Knight Cancer Institute’s resistance center, which will focus on acute myeloid leukemia.

“We want to extend the transient benefits of treatments that we see now into more lasting, durable responses,” she says, “And we want to avoid treating patients with drugs that won’t work.”

The NCI Drug Resistance and Sensitivity Centers Network includes five awards of $750,00o per year for five years

  • OHSU Knight Cancer Institute: Acute myeloid leukemia
  • Massachusetts General Hospital, Dana Farber Cancer Institute, Harvard Cancer Center: Colorectal cancer, melanoma, lung cancer
  • University of California San Francisco, Stanford University: Lung cancer
  • Mayo Clinic, University of Minnesota: Myeloma
  • Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Center: Prostate cancer

Acute myeloid leukemia, or AML, is the most common leukemia in adults. Less than a third of newly diagnosed AML patients survive beyond five years. The standard treatment is a drug combination developed about 40 years ago.

People with AML typically have more than one driver mutation and their leukemia cell populations are constantly evolving, with multiple lineages of cells competing for dominance. While one targeted drug may halt the effect of a cancer-associated gene mutation, new mutations can arise quickly to continue driving the progression of AML.

Resistance emerges by more than one mechanism. Mutations can change the shape of a cancer protein so that a targeted therapy drug can no longer interact with it. Cancer cells can also adopt new growth-signaling pathways to work around those blocked by targeted therapy drugs. And non-cancerous cells within the bone marrow microenvironment play a role in resistance by promoting the survival of leukemia stem cells.

Shannon McWeeney, Ph.D.
Shannon McWeeney, Ph.D.

The Knight Cancer Insitute team is going after all of these mechanisms.  “It’s a multipronged drive to get at what are the key genetic changes and signaling pathways that are responsible for resistance,” McWeeney said.

The researchers are building on a foundation that includes a long-running collaboration with The Leukemia & Lymphoma Society called Beat AML. That effort has included scientists at numerous other cancer centers, and created a cohort of more than 900 AML patient samples available for study.

In the resistance project, researchers will use the gene-editing tool known as CRISPR to create cancer cell lines that are resistant to five anti-cancer agents, and use them to identify all of the important genes involved in drug sensitization and resistance. Researchers will also use data from the Beat AML cohort to prioritize likely targets for agents that might enhance or restore drug sensitivity.

Anupriya Agarwal, Ph.D.
Anupriya Agarwal, Ph.D.
Jeff Tyner, Ph.D.
Jeff Tyner, Ph.D.

A second line of attack will focus on the bone marrow micro-environment, including inflammatory signaling and leukemia cell interactions with immune system cells and other non-cancerous cells. Goals include finding ways to identify patients likely to benefit from the immune therapy agents called checkpoint blockers. Anupriya Agarwal, Ph.D., an assistant professor in the OHSU School of Medicine and researcher with the OHSU Knight Cancer Institute, is leading this effort.

The third part of the project will test treatment combinations in AML patient samples. Jeffrey Tyner, Ph.D., an associate professor of cell, developmental and cancer biology in the OHSU School of Medicine, will head this work. Earlier this year, he and colleagues reported progress on a system for rapidly screening combinations of drugs to identify pairs of agents most likely to work synergistically against AML and other forms of leukemia.

The grant itself does not initiate clinical trials, McWeeney pointed out. But it will support testing drug combinations in patient-derived xenografts, in which tumor tissue from a patient is implanted into an immunodeficient mouse.

The new project will proceed in concert with two other big programs at OHSU recently funded by the NCI: the Proteogenomic Translational Research Center formed with the Pacific Northwest National Laboratory to identify biomarkers of drug response, and the CTD2 Center formed to apply advanced computational and functional systems biology approaches to better understand the pathways underlying drug resistance in AML and chronic lymphocytic leukemia.

Ideally, the resistance project will identify drugs or combinations of drugs worth advancing to clinical trials, such as the Beat AML Master Trial. In that multicenter study led by Knight Cancer Institute Director Brian Druker, M.D., researchers are providing rapid genomic testing of bone marrow samples, delivering results within seven days that could help direct choice of therapy. The trial is designed to be flexible, allowing investigators to open new treatment arms if data from other pre-clinical studies reveal promising results.


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Other OHSU contributors to the new D2RC center include Brian Druker, M.D., Motomi Mori, Ph.D., Cristina Tognon, Ph.D., Elie Traer, M.D., Ph.D., Marc Loriaux, M.D., Ph.D., Tamilla Nechiporuk, Ph.D., Tania Vu, Ph.D., Steve Kurtz, Ph.D., Ted Laderas, Ph.D., Guanming Wu, Ph.D., Beth Wilmot, Ph.D., Julia Maxson, Ph.D., Evan Lind, Ph.D., William Flemming, M.D., Ph.D., Bill Chang, M.D., Ph.D., Haijiao Zhang, M.D., Daniel Bottomly. Samantha Savage and Andy Kaempf.

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