Dr. Andrew Hsieh of the Human Biology Division is teaming up with colleagues at Fred Hutch and Memorial Sloan Kettering Cancer Center to make progress toward precision medicine for patients with prostate cancer. The team has garnered a two-year, $1 million Movember Foundation-PCF Challenge Award from the Prostate Cancer Foundation to examine how mutations in a molecular pathway critical to prostate cancer development affect drug response and could point the way to more tailored treatment.
Signaling pathways function a bit like very accurate games of molecular telephone. Cells rely on these pathways to respond appropriately to their environment (so that the right growth-controlling genes get turned on in response to a growth signal) — but disruptions in signaling pathways can have dire consequences. It’s been well-established that disruptions in one such pathway, the PI3K pathway, contribute to hormone deprivation-resistant prostate cancer — but this knowledge has not yet translated into effective treatments.
So far, research into anti-PI3K drugs “has not yielded a blockbuster drug,” said Hsieh. “It’s yielded small trials, which all failed,” he said.
But new insight into the mutations in the genes in the PI3K pathway provides new hope. Prostate tumors can have a wide array of mutations in these genes — but how these various mutations may affect tumor responses to different PI3K-targeted drugs is unknown.
Now, the two-year, $1 million PCF Challenge Award will allow Hsieh and MSK co-primary investigators Dr. Yu Chen and Dr. Brett Carver to combine their expertise to determine which drugs are effective against tumors with specific mutations and identify biomarkers that will enable oncologists to pair prostate cancer patients with the most effective treatment regimens.
The partnership between Hsieh, Chen and Carver sprang from scientific friendships forged during the early years of each scientist’s career, supported by PCF Young Investigator Awards. Hsieh brings expert knowledge of prostate cancer and the PI3K pathway and its effects on a critical cellular process: translating genetic material into proteins, our cells’ workhorses. Carver provides expertise in feedback regulation, the interplay between different molecular elements in the PI3K pathway. Chen, also an expert in the processes by which genes are turned on and off, has pioneered cutting-edge organoid systems that recreate prostate tumors and will allow the team to much more easily test the activity of various drugs against tumors with specific mutations.
Together the team will not only be able to provide clarity on which drugs are most effective against tumors with specific PI3K-pathway mutations, but how these specific mutations differentially affect how the pathway functions. While they will begin in Chen and Carver’s organoid systems, the scientists will also examine tissue from prostate tumors. Fred Hutch prostate cancer researchers and Seattle Cancer Care Alliance oncologists Drs. Pete Nelson and Heather Cheng will also contribute to the project.
“By developing 'new targets of opportunity' to eradicate prostate cancers with PI3K gene pathway mutations, Dr. Hsieh's team is bringing us closer to more potent and precise solutions for currently treatment-resistant prostate cancer,” said Jonathan W. Simons, MD, president and CEO of the Prostate Cancer Foundation.
The Prostate Cancer Foundation, which works to accelerate the world’s most promising prostate cancer research, received funds from the Movember Foundation’s 2015 US Campaign to support the 2016 Challenge Awards. The Movember Foundation is a global men’s health charity committed to helping men to live happier, healthier and longer lives.
The work will help answer the question of “why different drugs are more effective against tumors with different genotypes and phenotypes,” said Hsieh. By identifying which mutations reveal a vulnerability to a specific drug, the findings may have big impacts on patient care and clinical trial results. Oncologists will potentially be able to use the results to pair patients with the most effective drugs for their tumors, and researchers may improve clinical trial results by selecting those patients most likely to respond to a specific drug based on the mutations in their prostate tumors.
— Sabrina Richards
Dr. Melinda Biernacki, a senior hematology-oncology fellow at Fred Hutch Cancer Research Center, has been selected to participate in the 2016 Translational Research Training in Hematology, or TRTH, a joint program sponsored by the American Society of Hematology, or ASH, and the European Hematology Association. She is among 20 young investigators chosen to participate.
“TRTH has been a fantastic opportunity to get to know other translational hematology researchers from around the world. The program allows you to work closely with senior faculty, who’ve provided amazing mentorship. And it’s been terrific to meet and collaborate with other young scientists,” said Biernacki, who works in the laboratory of Dr. Marie Bleakley in the Clinical Research Division.
Biernacki’s research focuses on developing targeted immunotherapy for pediatric acute myeloid leukemia, or AML.
The TRTH program offers a rigorous, yearlong training and mentoring experience directed at helping junior scientists build successful careers in translational hematologic research.
Under the guidance of international leaders, participants learn the fundamental principles related to translational research, including developing a hypothesis and applying the scientific method to test that hypothesis in the laboratory. TRTH participants include medical, biomedical and pharmaceutical doctorate trainees who work in a hematology-related research environment as junior faculty or program leaders and have completed their fellowship training within the past three years.
This year’s TRTH program began with a weeklong course in March, which was designed to give participants a more profound understanding of translational research methodology. The course included didactic and interactive sessions and one-on-one faculty mentoring that focused on refining participants’ research proposals. TRTH participants convened again in June at the 2016 EHA Annual Congress in Copenhagen, where they attended small-group mentoring sessions. Biernacki and the other participants will present the status of their projects at the conclusion of the program at the 2016 ASH Annual Meeting, which will take place Dec. 3–6 in San Diego.
The TRTH program is made possible by generous support from the Wallace H. Coulter Foundation, Agios Pharmaceuticals, Incyte Corporation, Takeda Oncology and Gilead Sciences Inc.
“Talented researchers emerge from the TRTH program with the knowledge and professional network that will position them for success as they continue to grow their careers in the important discipline of translational research,” said ASH President Dr. Charles S. Abrams of the University of Pennsylvania. “We thank our partners and donors for contributing to the success of these 20 program participants who we have no doubt will make important discoveries that will change how we treat blood disorders.”
— Kristen Woodward
The Damon Runyon Cancer Research Foundation has named Dr. Shirleen Soh, a postdoctoral research fellow in the Fred Hutch Basic Sciences Division, a Damon Runyon fellow. She is among 17 postdocs nationwide to receive this prestigious award.
“The fellowship provides me generous support for four years to pursue my proposed research ideas,” said Soh, who is based in the laboratory of evolutionary and computational biologist Dr. Jesse Bloom, who sponsored her fellowship application. “Broadly, I’m interested in how viruses can adapt to new hosts. In my project, I aim to comprehensively identify the mutational paths by which avian [bird] influenza can adapt to the human host and determine the mechanisms of adaptation,” said Soh, who is jointly mentored by basic scientist and evolutionary biologist Dr. Harmit Malik.
Transmissions of influenza from avian and swine hosts to humans have the potential to result in pandemics with severe public health consequences, Soh said. Cancer patients, in particular, are disproportionately susceptible to complications arising from infection. Dissecting the pathways and mechanisms by which influenza can adapt to the human host will aid in the ability to predict and prevent pandemics resulting from infections being passed from animals to humans.
The Damon Runyon fellowship encourages the nation’s most promising young scientists to pursue careers in cancer research by providing them with independent funding to work on innovative projects that have the potential to impact cancer prevention, diagnosis and treatment.
Soh, originally from Singapore, received an undergraduate degree in biology from Harvard College and a doctoral degree in biology from the Massachusetts Institute of Technology.
— Kristen Woodward