Preclinical Testing of FLASH Radiotherapy and Immune Checkpoint Blockade Combination Therapy in Ovarian Cancer
Abstract
Despite current surgical and cytotoxic therapies, 80% of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and only 30% of patients survive 5 years following diagnosis. Our goal is to improve the overall survival of patients suffering from this devastating disease. I became committed to ovarian cancer research during my postdoctoral fellowship at Stanford where I identified and developed a targeted therapy for ovarian cancer based on inhibiting the GAS6/AXL signaling pathway that is upregulated during metastasis. Through my collaborations with gynecologic oncologists, I became aware of the unmet need for effective therapies in the management and treatment of ovarian cancer. Thus, I have directed my research efforts towards identifying and developing therapeutic strategies for the treatment of advanced ovarian cancer. I recently joined the Department of Defense Ovarian Cancer Academy as an Early Career Investigator where I continue to expand my collaborations with researchers and patient advocates in the ovarian cancer community. This pilot award is particularly exciting given that is has the potential to provide new treatment paradigms for patients with ovarian cancer. Radiation therapy plays a central role in curing cancer. In fact, in comparison to chemotherapy and targeted therapies, radiation therapy is responsible for the majority of cancer cures. Moreover, an emerging paradigm in cancer therapy is the use of radiotherapy to optimize antitumor responses to targeted immunotherapies. Radiotherapy can stimulate the immune system through the release tumor antigens and chemokines that promote antitumor immune responses. Clinically, the combination of radiation therapy and immunotherapy in patients with metastatic melanoma has led to durable systemic antitumor responses. However, the use of radiotherapy in the clinical management of ovarian cancer is limited due to the tumor spread throughout the abdomen and the potential for normal tissue toxicities associated with total abdominal irradiation. Current research efforts within the radiation oncology field are focused on developing therapeutic approaches to maximize the therapeutic index of radiotherapy by enhancing the tumor response and protecting normal tissues from radiotherapy damage. Recently, strategies have emerged to protect normal tissues by delivering ultrahigh dose-rate irradiation (FLASH). Conventional radiotherapy delivers radiation at doses of 3-4 Gy/minute. In contrast, FLASH radiotherapy delivers doses at a dose-rate of >40 Gy/second. A recent study has utilized FLASH radiotherapy in preclinical models of lung cancer to demonstrate that FLASH radiotherapy significantly enhances the therapeutic ratio of radiotherapy in the lung by sparing normal tissues from irradiation-induced acute apoptosis and fibrosis, while maintaining efficient lung tumor control. These studies suggest that FLASH radiotherapy may be an effective strategy to reduce the complications of radiotherapy while maintaining antitumor control. We have developed an experimental FLASH irradiator for small animals with which we have shown preliminarily that a dramatic reduction in mortality in mice following supralethal doses of abdominal radiation between FLASH vs. conventional delivery, indicating that this may be a general phenomenon across different normal tissue types. These findings raise the intriguing possibility total abdominal FLASH irradiation (TAI-FLASH) is an effective strategy to treat abdominal metastases from ovarian cancer and reduce the occurrence and severity of acute and late toxicities associated with total abdominal irradiation. Moreover, we hypothesize that the combination of TAI-FLASH with immune checkpoint blockade is a safe and effective strategy to achieve durable responses in patients with advanced ovarian cancer. Our therapeutic approach is a novel and will be particularly useful for recurrent ovarian cancer patien
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710042
Entities
People
- Erinn B. Rankin
Organizations
- Stanford University
- United States Army