Mortality rates in ovarian cancer (OvCa) patients have remained relatively unchanged in the last two decades. Across the United States, approximately 15,000-20,000 women die every year due to OvCa. In the U.S. military alone, more than 2,500 hardworking women and their immediate families have been diagnosed with OvCa or related endometrial cancers in the last 5 years. Besides, the OvCa diagnosis could potentially set up new, or worsen, pre-existing post-traumatic stress disorder (PTSD) among military families. The treatment options for high-grade ovarian serous carcinoma (HGSOC) patients include repetitive surgery and chemotherapy. The disease prognosis is very poor, and up to 85% of recurrent cancer patients develop chemoresistance and eventually die. This refractory state of HGSOCs is mainly due to the presence of redundant cellular cancer survival pathways and the existence of tumor heterogeneity. It is, therefore, critical to design and investigate alternate multi-facet biological therapies that would be highly selectively and effective against OvCa.

The proposed research focuses on antibodies and represents the Principal Investigator’s (PI’s) expertise. An antibody is a biological agent that can selectively bind and oppose the function of cancer-activating protein (antigen). Similarly, a bi-specific antibody can bind to two different cancer-specific proteins and have the inherent properties to block two cancer-causing cellular pathways at the same time. The bi-specific approach has proved clinically effective for acute lymphocytic leukemia (ALL), a blood cancer that, similar to OvCa, encounters very frequent chemoresistance and extremely low survival rates. Approximately 25% of relapsed ALL patients have received remission due to a bi-specific antibody that bridges the body’s immune killer cells next to blood cancer cells. I propose that similarly constructed bi-specific antibodies that not only engage the patient’s immune killer cells, but also encompass autonomous cell-death function with high OvCa selectively, will have direct pharmacological effect on the recurrent disease. Hence, I put forward to test a novel dual-specificity antibody that targets: (1) an HGSOC-enriched protein called folate receptor alpha-1 (FOLR1) and (2) OvCa epithelial tissue-enriched cell death-activating death receptor-5 (DR5). FOLR1 is overexpressed (multiple fold) in >90% of HGSOCs and will function to anchor the bi-specific antibody molecule selectively in the OvCa tissue. As a result, the second components of this dual affinity molecule (that activate DR5 protein) will engage and instigate an autonomous cell death pathway selectively in a FOLR1+ population. Dying OvCa cells will then generate a comprehensive immune memory via an enhanced phagocytic activity that is highly dependent on the bispecific antibody. This combinatorial targeting approach offers a promising path for safe and effective disease remission against a chemoresistant patient population and is within the research and career development plan of the PI.

This project is extremely important, not only from an investigative translational research perspective for generating effective therapies, but also to provide a strong foundation for the young PI’s laboratory to be recognized as expert in this arena and to develop an important niche by building collaboration with other academy members. In addition, a PI with expertise in antibody engineering and biopharmaceutical-relevant immune technologies will be a valuable resource to other academy members. Proposed research will generate solid mechanistic biology of bi-specific molecules and will establish a novel therapeutic approach for anchor-directed selective cell toxicity to malignant cells that can also be applied to other solid cancers. The proposed research is directly applicable to the treatment of refractory late-stage FOLR1+ HGSOC patient populations (>70% of total OvCa cases) in improving PFS and overall survival (OS). Unlike chemotherapy, this biological approach has great potential to be clinically beneficial, since toxicity will be significantly reduced in healthy p53+ and low FOLR1+ expressing liver, heart, intestine and other epithelial cells. Furthermore, if proposed studies would display reduced toxicity combined with high efficacy in animal and PDX model studies, the lead molecule potentially should provide disease-related outcomes to HGSOC patients within 3-5 years. In addition to generated mechanistic comprehensive data and a few high-profile publications in the field, this study will advance our knowledge of targeted bi-specific cancer therapies that indirectly instigate the immune system to avoid cytokine storm and other clinical safety issues.

Finally, the financial support from this Early-Career Investigator Award will serve as the gold standard toward the completion of this project. If successful, this approach will significantly improve and stabilize the PFS and OS of hardworking and respected military Service members and their families. As stated earlier, among ~ 2500 U.S. military women and their families that are diagnosed with OvCa, many of them also develop PTSD. Therefore, OvCa remission will also potentially improve cancer-related PTSD in these military patients. As a young investigator, it will be my privilege to lead this project to find the potential cure for those who serve, protect, and defend this country, so that all civilians can feel proud and safe in their homes.