Trainee Spotlight: Marie Danielle Ralff
As a child, I loved the Franklin Institute. In fact, I loved it so much that for three years in a row my parents held my birthday parties at the museum. This might have been the earliest sign that I was destined to become a scientist (and that I was a nerd through and through!). With the support of some amazing middle school and high school science teachers along the way, I ended up as an undergraduate student at the Pennsylvania State University studying biochemistry and molecular biology. As I entered my third year, I was faced with the same question as many other science majors: did I want to apply to medical school or to graduate school? I agonized over the question sufficiently, and ultimately decided that I would apply to medical school. The research I had participated in during my undergraduate years was basic science-focused, and while it was interesting, I found that I was more inspired by the time I spent with patients volunteering at the Mount Nittany Hospital. I started medical school at Temple University in August of 2013. It didn’t take long for me to realize something was missing, and that something was research. I was lucky enough to have an opportunity to transfer into the Temple MD/PhD program and joined Dr. Wafik El-Deiry’s lab in the summer of 2015. As a physician scientist, Dr. El-Deiry works tirelessly to translate the findings of his lab into the clinic. His genuine enthusiasm and excitement for both science and medicine turned out to be exactly what I was looking for. My short-term goal is to pursue residency and fellowship training as a medical oncologist after I graduate from the MD/PhD program. My long-term goal is to practice as a physician scientist, seeing patients while also running a translational research lab of my own.
Our lab studies ONC201, a member of a new class of anti-cancer compounds known as the imipridones. The El-Deiry lab originally identified ONC201 in a luciferase reporter screen as a p53-independent transcriptional inducer of TNF-related apoptosis inducing ligand (TRAIL). TRAIL is a protein typically expressed on immune cells that binds to cell surface death receptors DR4 and DR5, inducing cell death in tumor cells but not normal cells. Initially called TIC10 (TRAIL-inducing compound 10), ONC201 was selected as the lead candidate from the screen following its success in preclinical studies and has since completed its first-in-human clinical trial and is currently being tested in phase II trials across the United States. My project focuses specifically on the effects of ONC201 in breast cancer. Breast cancer is the most commonly diagnosed cancer in women in the United States today, and the second leading cause of cancer-related death. With the exception of a subset of triple negative breast cancers (TNBCs), the majority of breast cancers have been shown to have intrinsic resistance to TRAIL-mediated apoptosis. Different mechanisms of TRAIL resistance have been characterized in breast cancers, including low surface expression of death receptors and high levels of IAP and Bcl-2 family anti-apoptotic proteins. ONC201 has been previously shown to affect these resistance mechanisms, increasing cell surface DR5 expression and decreasing expression of anti-apoptotic proteins. These observations led to a hypothesis that ONC201 may be efficacious in both TNBC and non-TNBC cells.
My manuscript, recently published in Molecular Cancer Therapeutics, reports that ONC201 shows efficacy in TNBC and non-TNBC cells through both TRAIL- dependent and TRAIL-independent mechanisms. A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induced caspase-8 cleavage and cell death that was blocked by a TRAIL-neutralizing antibody. Importantly, the pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an anti-proliferative effect but does not induce apoptosis. All non-TNBC cells are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. This is the first demonstration of the efficacy of ONC201 across a spectrum of breast cancer cell lines, including non-TNBC cells that are TRAIL resistant. Overall, our findings describe the heterogeneous responses observed and provide a preclinical rationale for testing of the compound against breast cancers in the clinic.
The current goal of my project is to build on these initial observations and elucidate the mechanisms responsible for the observed heterogeneous responses of breast cancer cells to imipridone compounds such as ONC201. The first aim of the project is to explore the differences in the activation of the extrinsic apoptosis pathway between breast cancer cells that do undergo apoptosis with the compounds versus those that do not. Identification of a block in pathway activation will allow for rational selection of drug combinations that can be used to overcome this block and sensitize to the TRAIL inducing effects of the imipridones. A second aim of the project is to unravel the mechanism responsible for the anti-proliferative effects of the imipridone compounds.
Ralff, M.D., et al., ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms. Molecular Cancer Therapeutics, 2017 Jul;16(7):1290-1298