SEATTLE — March 22, 2019 — Fred Hutchinson Cancer Research Center’s latest findings in immunotherapies, nanoparticles to deliver gene therapy, the genetic underpinnings of cancer, insights on health disparities and more will be showcased at the annual meeting of the American Association for Cancer Research. The conference, “Integrative Cancer Science — Global Impact — Individualized Patient Care,” will be held March 29–April 3 in Atlanta. See highlights below.
Reporters seeking additional information, interviews or referral to experts who can comment on other news at AACR can contact the Fred Hutch media relations team: email@example.com, 206.667.2210. For help at AACR, Jill Christensen on the media relations team will be at the conference and can assist with scheduling interviews: firstname.lastname@example.org, 408.596.6887 (cell).
NextGen Stars spotlight: Functional analysis of 5’UTR mutations in prostate cancer reveal dynamic regulation of clinically relevant gene networks. The AACR NextGen Stars program increases the visibility of early-career scientists and supports their professional development and advancement. In an April 1 session on site-specific cancers, Dr. Yiting Lim, a postdoctoral research fellow working with Dr. Andrew Hsieh at Fred Hutch, will present what is believed to be the first comprehensive study of 5’UTR mutations in prostate cancer patients. The “untranslated region” of the genome, called 5’UTR, does not code for genes themselves but instead regulates gene expression. Lim examined 5’UTR mutations in more than 200 prostate cancer patients. Her findings reveal that the mutations affected how proteins are made and how that, in turn, drives prostate cancer growth. The study is a first step toward targeting the mutations, which could potentially be used in new cancer therapies.
Blood tests to detect cancer and guide treatment. An emerging diagnostic approach known as the liquid biopsy has the potential to offer an easier way to detect cancers and guide treatment compared with the standard of removing a portion of tissue from patients and testing it for cancer markers. A study to be presented April 2 at AACR on the reliability of one such test to detect cancer markers in blood samples from newly diagnosed lung cancer patients has already received attention in advance of the meeting. Fred Hutch experts are developing similar tests for lung and breast cancer as well as other biomarker discovery research and are available to comment on the significance of the findings to be presented at AACR.
Updates in cancer immunology research. Dr. Phil Greenberg, one of the two editors-in-chief of AACR’s Cancer Immunology Research, will speak at a March 30 roundtable on cancer immunology and at a March 31 Cancer Immunology Working Group Town Hall Meeting and Networking Reception. Greenberg, head of the Program in Immunology at Fred Hutch, led some of the earliest studies showing how T cells can recognize and eliminate malignant cancer cells and is an expert on engineering T cells to fight cancer. In a Fred Hutch Q&A last fall, Greenberg spoke about where cancer immunotherapy is now and where it’s going.
Deconstructing tumor-infiltrating T-cell heterogeneity through analysis of antigen specificity. A leading researcher in human T-cell immunology, Dr. Evan Newell of Fred Hutch, will provide one of three presentations in a major AACR symposium on organ-specific immunity, to be held April 1. Employing new methods for identifying and profiling T cells that are specific for tumor-expressed antigens, Newell’s research aims to provide a better understanding of how the immune cells recognize disease. He also seeks to vastly increase the number of cancer-related T-cell antigens that can be studied. Newell says immunology is leading to major changes in the way diseases are managed, but successes in cancer immunotherapy have been inconsistent, making it crucial to identify T-cell subsets relevant to various manifestations of the disease.
Using T-cell engineering plus triple checkpoint blockade to enhance the efficacy of adoptive immunotherapy in ovarian cancer. Although ovarian cancer and other solid tumors have formidable immune-suppressing defenses that pose a major challenge for cellular immunotherapies, the engineering of immune T cells to target proteins uniquely overexpressed in these cancers is a promising new strategy being pursued in the lab of Dr. Philip Greenberg at Fred Hutch. In a poster to be presented April 2, Dr. Kristin Anderson, a postdoctoral researcher in Greenberg’s lab, will describe recent studies of candidate immunotherapy targets, focusing on mesothelin, or MSLN, which contributes to invasive progression and malignancy in ovarian cancer. By activating MSLN-specific T cells and using three antibodies for checkpoint blockade — anti-PD-1, anti-Tim-3 and/or anti-Lag-3 — the researchers have improved the ability of the T cells to make the cytokines that kill tumor cells. Because many solid tumors overexpress these proteins and MSLN, this multi-checkpoint blockade strategy with engineered T cells may have the ability to enhance the efficacy of engineered adoptive T-cell therapy against other malignancies.
Neutrophils contribute to anti-PD1 treatment failures in NSCLC. Research led by Dr. McGarry Houghton, a Fred Hutch lung cancer immunologist, demonstrates how tumors co-opt neutrophils for their own survival and proliferation needs. Although the immune cells can be potent infection-fighters, tumors turn them to their advantage. That’s part of the reason why checkpoint inhibitor drugs — which unleash the molecular brakes of the immune system, enabling it to attack cancer — work for only a portion of patients. Houghton’s team is studying the mechanisms that turn neutrophils traitorous, with the goal of finding ways to keep the cells from helping cancer grow. The effort could help make checkpoint-inhibitor therapies effective in more patients. He will present this work during a March 30 AACR educational session on neutrophils.
Programming tumor-clearing macrophages with targeted in situ gene therapy. In an April 3 poster session, Dr. Fan Zhang, a postdoctoral fellow in the laboratory of Dr. Matthias Stephan, will explain how Fred Hutch researchers are using nanoparticles to genetically reprogram macrophages — a type of immune cell that can protect tumors — so that the cells can attack tumors. The approach works by having the nanoparticles bind to the macrophages in the tumor and then that triggers signals for immune-boosting genes that enable the macrophages to engulf tumor cells. The researchers have tested the strategy in mouse models of ovarian tumors, lung metastases and brain tumors. They are now working toward clinical trials. Ultimately, the technology could be used to help make tumors more vulnerable to therapies without disrupting patients’ overall immune function.
Precision medicine and genetics
Epigenetic drivers and vulnerabilities in small-cell lung cancer. Small-cell lung cancer is one of the most aggressive of all cancer types. Although many patients respond well to chemotherapy, the cancer usually returns in a chemo-resistant, recalcitrant form and little can be done. Dr. David MacPherson is part of a National Cancer Institute-supported consortium studying the disease, and his lab is now devoted solely on this type of tumor. As part of an April 1 AACR session on small-cell lung cancer, MacPherson will discuss his research on the biology of mutated genes that enable the survival and proliferation of small-cell lung cancer and efforts to develop strategies to reverse effects of these gene mutations. His group observed that many tumors have mutations in molecules that regulate chromatin, DNA’s packaging system. Recent studies suggest that a subset of cancers may be sensitive to an experimental class of drugs targeting one such molecule, LSD1. His research also sheds light on why a particular chromatin regulating gene, CREBBP, is a target of inactivating mutations in this tumor type. Ultimately, MacPherson envisions targeted treatments for different subsets of small-cell lung cancer based on what gene mutations are present.
Genetic pathways in lung cancer. Two AACR presentations by researchers in the lab of Dr. Alice Berger, a cancer geneticist and lung cancer researcher, will showcase her team’s latest findings in understanding genetic mutations that lead to cancer. The goal of the work is to better understand the genetic machinery and molecular alterations that are unique to an individual patient’s tumor and then use those characteristics to determine which therapy would be most effective.
· In an April 1 cancer genomics minisymposium, Dr. Athea Vichas — a postdoc in the Berger Lab — will discuss how mutations in a signaling pathway called RIT1 (Ras-related small GTPase) were linked to disruptions in another pathway called Aurora kinase. The findings from cancer cells in a lab dish suggest that blocking Aurora kinase with existing therapies would work for people with lung adenocarcinoma with RIT1 mutations.
· In a poster presentation April 2, graduate student April Lo will share results from a high-throughput RNA sequencing screen used to identify thousands of RNA-splicing events, which go awry in lung adenocarcinoma and other cancers. The analysis showed that one gene, RBM45, may alter cell-cycle patterns by regulating alternative splicing. The discovery will allow the researchers to delve deeper into how to target the pathway for a future therapy.
Prospects for epigenetic therapy for breast cancer. An expert in the epigenetics of breast cancer, Dr. Nancy Davidson, senior vice president and director of the Clinical Research Division at Fred Hutch, will lead an AACR symposium on epigenetic therapies for solid tumors and present information on the use of this approach for breast cancer. The symposium will review the lessons learned from the first generation of epigenetic therapeutic trials, present data on ongoing trials and preview future efforts in gastrointestinal cancers, lung cancer and breast cancer. Davidson, a former AACR president, is also president and executive director of Seattle Cancer Care Alliance, the Hutch’s clinical care partner. Beyond her work in breast cancer research and epigenetics, she also has a strong interest in addressing health disparities in breast cancer.
Breast cancer incidence and hormone therapy use before and after the Women’s Health Initiative (WHI) estrogen (E) plus progestin (P) trial by race/ethnicity. In 2002, Women’s Health Initiative researchers found an increased risk for lobular breast cancer, heart disease and stroke among women in the study who were randomly chosen to receive estrogen and progestin therapy. Over the decades of the initiative, Dr. Ross Prentice and Dr. Garnet Anderson and other researchers at Fred Hutch have managed and analyzed the wealth of WHI data as leaders of WHI’s Clinical Coordinating Center. During an April 2 late-breaking research session at AACR, the WHI team represented by Dr. Rowan Chlebowski of Harbor-UCLA Medical Center will share the latest insights on hormone treatment and breast cancer and how it compares to race and ethnicity. The abstract is embargoed and will be available on the AACR website at 3 p.m. ET, March 29.
NOTE: Fred Hutch and its scientists who contributed to these discoveries may stand to benefit from their commercialization. See links above to AACR abstracts for more details on individual researchers’ disclosures.
The clinical trials referenced above involve investigational products and/or therapies that have not been approved for commercial marketing by the U.S. Food and Drug Administration or any other regulatory authority. Results may vary and encouraging results from early-stage clinical trials may not be supported in later-stage clinical trials. No conclusions should be drawn from the information in this report about the safety, efficacy or likelihood of regulatory approval of these investigational products and/or therapies.
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