OHSU scientists represent at AACR

A Knight Cancer Institute scientist took the reins as president of the American Association for Cancer Research. Another joined the prestigious ranks of AACR fellows. And a multitude of faculty, postdocs and grad students presented new findings at the organization’s annual meeting in New Orleans this week.

On Monday, Lisa Coussens, Ph.D., was inaugurated as president of the organization for 2022-2023. Coussens is associate director for basic research in the Knight Cancer Institute and professor and chair of the Department of Cell, Developmental, and Cancer Biology in the OHSU School of Medicine. Her election to lead AACR was announced last April.

Photo: AACR President Lisa Coussens, Ph.D., (center) talks with constituents. (OHSU/Amanda Gibbs)“A major goal of mine is mentoring junior scientists to successful completion of their goals,” Coussens told attendees at the AACR meeting. “What I hope to achieve with the AACR is to utilize the breadth of diversity of the organization to create a framework for junior scientists that can be integrated across institutions.”

Gordon Mills, M.D., Ph.D., was among the 33 international scientific leaders honored as incoming Fellows of the AACR Academy. He also co-chaired a session on emerging anticancer agents and gave an update on Knight Cancer researchers’ efforts to target adaptive responses to therapy in cancer. Mills is director of precision oncology for the Knight Cancer Institute, and he holds the Wayne and Julie Drinkward Endowed Chair in Precision Oncology in the OHSU School of Medicine.

Solving drug resistance

Meeting officials highlighted ovarian cancer research by OHSU’s Sanjay Malhotra, Ph.D., who chaired an educational session on drug resistance. Malhotra is a professor in the Department of Cell Developmental and Cancer Biology, and director of the Knight’s Center for Experimental Therapeutics. His lab is developing a natural product-derived agent, SU056, that inhibits the protein YBX-1, an RNA binding protein and key regulator of pre-mRNA alternative splicing and processing. In animal models, SU056 treatment inhibits tumor progression and metastasis and sensitizes ovarian cancer cells to treatment with the drug paclitaxel.

Dhanir Tailor, Ph.D., a postdoctoral fellow in Malhotra’s lab, presented more detail on SU056 as a potential therapy for ovarian cancer. In another session, Tailor shared preclinical data on a drug meant to stop triple-negative breast cancer. The small molecule, CET12, binds to the glycolytic enzyme ENO1. In mouse models, the treatment inhibits tumor progression and metastasis.

AACR President Lisa Coussens, Ph.D., left, meets with Amy Moran, Ph.D. (Amanda Gibbs/OHSU)

Knight Cancer scientist Amy Moran, Ph.D., gave an update on research suggesting that androgen-blocking drugs could make immunotherapies work more consistently in men with prostate cancer. Moran’s lab found that T cells within tumors and healthy tissue express androgen receptors and that exposure to androgen hormones effectively disables the T cells. The researchers showed that blocking androgen signaling sensitizes multiple tumor mouse models to immune checkpoint inhibitors by directly enhancing CD8 T cell function. Moran, an assistant professor of cell, developmental and cancer biology, also chaired a session on the effects of sex on tumor development and response to therapy.

Ece Sebnem Eksi, Ph.D., a postdoctoral scholar in CEDAR, shared results giving a deeper understanding of the active gene regulatory networks in primary prostate tumors, critical for molecular stratification of the disease. Her team sequenced the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumors, revealing shared chromatin features among low-grade prostate cancer cells that are lost in high-grade tumors.

Taking on critical needs

Graduate student Isabel English described the development of a genetically engineered mouse model of pancreatic cancer that recapitulates the diverse and aggressively spreading nature of the human disease. She showed how the model can be used to study the role of deregulated MYC expression in metastatic behavior, immune phenotypes, and therapeutic response. English works in the lab of Rosalie Sears, Ph.D., professor of molecular and medical genetics.

Sears lab graduate student Gabriel Cohn shared data suggesting that MYC signaling is a potential target for treating drug-resistant pancreatic cancer. In experiments using cell lines from patient tumors, the researchers found that the drug olaparib significantly increases accumulation of the transcription factor MYC at the nuclear pore to promote DNA repair during replication stress. Kevin MacPherson, another Sears lab grad student, presented findings on the role of the neuronal gene repressor RE1-Silencing Transcription Factor, or REST: how it controls neuroendocrine gene programs in pancreatic cancer, and how loss of REST promotes gemcitabine resistance and cancer growth.

Cachexia, an extreme weight loss syndrome, is highly prevalent in patients with pancreatic cancer. Paige Arneson-Wissink, Ph.D., shared data showing that interleukin-6 derived from tumors impairs the liver’s response to undernutrition in pancreatic cancer cachexia, and that restoration of liver ketone metabolism is a promising avenue for preventing muscle atrophy in cachexia. Arneson-Wissink works in the lab of Aaron Grossberg, M.D., Ph.D., assistant professor of radiation medicine.

Beth L. Worley, Ph.D., another postdoc in the Grossberg lab, detailed how blocking the RNA-binding protein called HuR might provide a new way treat cachexia caused by pancreatic cancer. In a mouse model of the disease, increased HuR activity was found to mediate adipose anabolism. Inhibition of HuR restored lipogenesis in refed animals, and allowed them to regain fat pad mass.

Graduate student Grace A. McCarthy made the case that inhibiting HuR could potentially make pancreatic cancers more vulnerable to chemotherapy by reducing fibrosis. Her team in the lab of Jonathan Brody, Ph.D., professor of cell, developmental and cancer biology, discovered that HuR from pancreatic tumors effects neighboring non-cancer cells. In mouse experiments, tumors with the HuR gene knocked out showed a decrease in markers of cancer-associated fibroblasts and pancreatic stellate cells, as well as a decrease in collagen deposition.

Surprise findings

Breast cancers diagnosed within five years of giving birth are much more likely to metastasize and become deadly, and liver biology is implicated in the increased risk, according to findings shared by Zhenzhen Zhang, Ph.D., an assistant professor in the Division of Oncological Sciences. Liver was the first site of metastasis in 46% of women with postpartum breast cancers who progressed to metastasis.

In another session, Zhang presented results from one of the first studies to assess how neighborhood socioeconomic status contributes to breast cancer mortality in young women of differing ethnic backgrounds. Higher census tract-level socioeconomic position, defined as ≥60% of the population having a bachelor’s degree, is associated with a significantly decreased risk for breast cancer mortality at all stages of diagnosis in woman 25 to 49 years old.

Epigenetic adaptation is a major contributor to drug resistance in acute myeloid leukemia treated with kinase inhibitor drugs. William Yashar, an M.D./Ph.D. student in the lab of Ted Braun, M.D., Ph.D., presented evidence that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the response to a FLT3 kinase inhibitor, providing rationale for a clinical trial of the combined treatment.

Several other OHSU scientists presented at the meeting. Jeremy Goecks, Ph.D., talked about deep learning applications in multiplex tissue imaging for precision oncology; Naoki Oshimori, Ph.D., described a cancer stem cell-driven signaling loop for the niche formation; Jonathan Brody, Ph.D., gave his perspective on the power of the surgeon-scientist team. Courtney Betts, Ph.D., described building a multiplexed imaging atlas of the tumor-immune microenvironment in pancreatric cancer for advancing discovery and immune monitoring. And Laura Heiser, Ph.D., presented systems approaches to targeting cell states in the tumor ecosystem.

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