“I believe we can do this because there are so many breakthroughs on the horizon in science and medicine….I will eliminate the barriers that get in your way, that get in the way of science, research and development.” – Vice President Joseph Biden
Vice President Biden and his wife, Dr. Jill Biden, capped off the 2016 Annual Meeting of the American Association for Cancer Research (AACR) by rallying the scientific community behind the Administration’s “Cancer Moonshot” initiative. Attendees of the conference, the largest gathering of cancer scientists from across the globe held in New Orleans April 16-20, were a captive audience for the Bidens’ remarks. Not only will the initiative infuse another $1 billion into the National Institutes of Health research budget, but it also promises to spark collaboration, data sharing and research advancements like never before. The address additionally served as a heartfelt “thank you” to those scientists on the front lines of deciphering the biology of cancer and improving cancer prevention, detection, diagnosis and treatment.
The thousands of discoveries reported at the AACR conference served as evidence that there is reason to be confident in the intent and promise of the “moonshot.” And work from many researchers at the University of Chicago Medicine Comprehensive Cancer Center earned recognition on this international scientific stage. The following are some highlights from our faculty, staff and trainees.
In recent years, harnessing an individual’s immune system for anticancer therapy has gained attention and achieved considerable success for some types of cancer. Advances at this year’s AACR meeting centered upon expanding the types of cancers that may benefit from this approach, predicting a tumor’s responsiveness to immunotherapy, and identifying therapies that are even more potent when combined with immunotherapy.
Thomas Gajewski, MD, PhD, chaired a major symposium called “Cancer Immunotherapy: Small Molecule Approaches,” where he presented his group’s latest work identifying a T cell-inflamed molecular signature that predicts a tumor’s responsiveness to immunotherapy. He also discussed strategies to convert tumors that do not have this signature into responsive cancers. Gajewski described host signaling networks, such as the beta-catenin pathway and others, that control the response, as detailed in a recent study published in Nature.
Another presentation in the session described a collaborative study by Gajewski and scientists at Aduro Biotech and Novartis. This time, researchers used a new drug to activate the STING pathway in the tumor microenvironment, or the immune cells, blood vessels, signaling molecules and supporting three-dimensional matrix in which tumors reside. The new drug caused tumors in preclinical models to markedly shrink, and data from the study lay the foundation for a planned phase I clinical trial.
Gajewski also chaired an education session on the “Microbiome and Cancer Immunotherapy” focused on how the collection of bacteria in an individual’s body, known as the microbiome, impacts immunotherapy. In that session, his fellow Leticia Corrales, PhD, discussed their discovery that a particular strain of bacteria (called Bifidobacterium) improved the ability of mice with melanoma to respond to drugs called immune checkpoint inhibitors, such as anti-PD-L1 antibodies. Some of these data were published recently in the journal Science.
The results of a multicenter, phase III immunotherapy study, in which Everett Vokes, MD, serves as an investigator, were presented at the “Clinical Trials Plenary Session.” In this trial, nivolumab, an anti-PD-1 antibody, improved overall survival in a subset of patients with advanced head and neck cancers, creating a new standard of care treatment for these patients.
Finally, a collaborative project led by Wenxin Zheng, PhD, in the laboratory of Ralph Weichselbaum, MD, and involving Mitchell Posner, MD, and Michael Spiotto, MD, described the use of radiation therapy to increase the sensitivity of pancreatic cancer to immunotherapy. Weichselbaum also participated as a panelist in the AACR Radiation Science and Medicine Working Group Town Hall Meeting.
Tumor Microenvironment and Immunology
An increased understanding of how the tumor microenvironment contributes to how tumors grow and spread is necessary to develop innovative ways to destroy tumor cells and prevent metastasis.
Daniel Rabe, a senior PhD student and recipient of an AACR Scholar-in-Training Award, presented his work on the role of the microenvironment in triple-negative breast cancer, a project from the laboratory of Marsha Rosner, PhD, in collaboration with Lev Becker, PhD, Yoav Gilad, PhD, and Thomas Krausz, MD. He found that the raf kinase inhibitory protein (RKIP), which acts to suppress cancer metastasis, also controls infiltration of tumor-associated macrophages, a specific subtype of immune cells, into these tumors. He also identified one potential molecule responsible for this effect, a cytokine called CCL5, that could be targeted therapeutically.
Another PhD student, Lindsey Ludwig, working in the laboratory of James LaBelle, MD, PhD, received an AACR Women in Cancer Research Award for her findings on the regulation of immune cell behavior in tumors. Using genetically engineered preclinical models, she found that members of a family of proteins involved in programmed cell death (called BH3-only proteins) are required for distinct features of immune B cell and T cell growth, maintenance and death.
Novel and more effective approaches to cancer therapy require research aimed at identifying new molecular targets, and refining strategies for targeting and uncovering mechanisms of resistance to current treatments.
A multi-investigator study led by postdoctoral fellow Sean Fanning, PhD, working with Geoffrey Greene, PhD, identified a molecular switch that controls the action of the estrogen receptor (ER) in breast cancer. They found that a drug called bazedoxifene inhibits certain ER genetic variants found in patients with more potency than other anti-estrogen breast cancer therapies, including tamoxifen and raloxifene. Fanning’s research is funded by a fellowship from Susan G. Komen, and he received a John Shevell Travel Award to present his work at the conference.
In an oral session on “Recent Advances in Diagnostics and Therapeutics,” Suzanne Conzen, MD, presented work from her team on activation and crosstalk among ER and other nuclear hormone receptors in breast cancer. Conzen described a complex interplay between ER and the NR3C class of nuclear hormone receptors (specifically the glucocorticoid receptor, progesterone receptor and androgen receptor) and how combinations of these proteins control gene expression in tumor cells. These findings have important implications on targeting the receptors therapeutically and the subtypes of breast cancers that might be amenable to targeting.
Another team led by postdoctoral fellow Aritro Nath, PhD, in the laboratory of R. Stephanie Huang, PhD, and involving Michael Thirman, MD, Lucy Godley, MD, PhD, and Richard Larson, MD, presented their work developing response predictors for a class of drugs (tyrosine kinase inhibitors) commonly used to treat chronic myeloid leukemia. They demonstrated the power of using comprehensive gene expression profiling gathered over the course of treatment to identify pathways or molecular features associated with drug response.
David Grdina, PhD, in a collaborative project with Weichselbaum, reported the identification of a tumor response to very low doses of ionizing radiation. This response, which was mediated by the protein survivin, might improve outcomes associated with increased use of imaging procedures in radiation therapy.
In the “Clinical Trials Symposium,” results from the phase II I-SPY 2 breast cancer trial involving Rita Nanda, MD, showed improved responses with a combination of the antibody-drug conjugate T-DM1 and the anti-HER2 antibody pertuzumab for HER2-positive breast cancer compared to standard therapy.
Jason Luke, MD, chaired a minisymposium session on “Preclinical Development of Potent and Selective Inhibitors” that described several promising new agents in the targeted anticancer therapy pipeline, including tyrosine kinase inhibitors.
A biomarker is some feature that can be measured as an indicator of cancer presence or response to treatment. Development of more reliable and sensitive biomarkers is critical for improving cancer detection and monitoring outcomes associated with therapy.
Albert Yeh, a resident working with Olufunmilayo Olopade, MD, and Maryellen Giger, PhD, presented the results of a multidisciplinary study involving breast cancer radiology and genomics in a minisymposium on “Genomic Landscapes.” In the study, also involving Gregory Karczmar, PhD, Hiroyuki Abe, MD, and Jeffrey Mueller, PhD, Yeh used powerful computational methods to combine radiomics (high-throughput extraction and analysis of magnetic resonance imaging features) and genomic features. The goal of this work is to gain detailed biological information using a non-invasive imaging approach.
In two additional studies involving Olopade presented in the “Biomarkers to Direct Cancer Therapy” minisymposium, researchers assessed the effectiveness of new biomarkers in locally advanced breast cancer through the I-SPY 2 early-stage clinical trial. In the first, a 7-gene DNA repair-deficiency signature (also called the PARP inhibitor signature) was shown to predict how a tumor responds to a drug combination of PARP inhibitor (veliparib) and chemotherapy (carboplatin). The team also found that combining this biomarker with another gene signature (MammaPrint) may make it even easier to predict response to therapy in a subset of triple-negative breast cancer patients. The second study identified gene and pathway differences upon classification into “high” and “ultrahigh” risk groups based on the 70-gene MammaPrint prognostic signature. Classification with this signature helped predict sensitivity to chemotherapy.
Mark Ratain, MD, participated in a debate-like forum on the use of molecular signatures and genomic predictors for assessing risk of recurrence and metastasis for localized prostate cancer.
A detailed understanding of the molecular networks that drive tumor cell growth and spread provides the basis for developing new cancer therapies and biomarkers. Therefore, the AACR Annual Meeting highlights new discoveries that unravel how tumor cells are wired.
Several presentations from Yuskuke Nakamura, MD, PhD, and his team, reported novel protein modifications of well-characterized signaling proteins in cancer cells. Studies from Yuichiro Yoshioka, MD, and Xiaolan Deng, PhD, showed that lysine methylation of beta-catenin and AKT-1 significantly affected the activity and cellular localization of these oncogenic proteins. Fellow Theodore Vougiouklakis, MD, demonstrated that the ERK1 kinase is also methylated in tumor cells, thereby enhancing growth-promoting activity. All of these modifications represent new opportunities for therapeutic targeting.
Kay Macleod, PhD, and her PhD student Maya Springer presented new findings from a recent publication that examined the role of mitophagy, the process by which damaged mitochondria are degraded and removed from the cell, in cancer metastasis. Macleod and colleagues found that loss of a mitophagy regulator protein called BNIP3 accelerated the development and metastasis of pancreatic cancer in a mouse model, and manipulation of BNIP3 expression in human pancreatic cancer cells altered tumor cell growth.
Work from PhD student Ashley Sample in the laboratory of Yu-Ying He, PhD, identified a novel interaction between the p62 autophagy protein and cyclooxygenase-2 in ultraviolet radiation-induced skin cancer. Since both proteins had been known to be important in skin cancer previously, this study uncovers a possible new molecular mechanism responsible, and one that could be exploited for therapy.