Funded in Collaboration with Stand Up To Cancer (SU2C)
Clinical oncology has entered an era of personalized molecular diagnosis and targeted therapy. This means treatments are tailored to each patient based her tumor’s histopathological and genetic characteristics. Such personalized treatment often involves a combination of multiple active agents to treat one tumor. In estrogen receptor positive (ER+) breast cancers, the three most promising classes of treatments are hormonal therapy, PI3K pathway inhibitors and cell cycle inhibitors.
Although patients derive benefit from such treatment, for most of the advanced ER+ breast cancers, the tumors respond initially but then stop responding, which is called “resistance” to therapy. Unfortunately, this resistance results in death in most cases of advanced breast cancer. Treating these cases requires developing novel therapeutic strategies to overcome the resistance based on an understanding of the mechanisms of resistance.
In this project, we leverage the leading edge technology of high-throughput whole-genome screening to discover mechanisms of resistance to each of three classes of drugs and all of their combinations. We also characterize the identified genes and their function in a variety of breast cancer cell types and mouse models. The knowledge of resistance to treatment obtained through this project will guide our effort to design more effective combinational therapeutics to overcome resistance. Ultimately, this work will be translated to benefit most of the patients with ER+ breast cancers.
Through these studies we hope to identify the transcription factors critical for the transformation of human breast cells, and to develop specific inhibitors of these transcription factors. Such transcription factor inhibitors may be novel therapeutic agents for the prevention and treatment of breast cancer.
Fewer than 5% of adult cancer patients in the United States are enrolled in clinical trials. In addition, minorities constitute a small proportion of individuals participating in cancer studies. These strikingly low figures delay scientific advances, limit generalizability of trial results, and limit patient access to cutting-edge therapies. Proposed reasons for low accrual include lack of study availability, stringent eligibility criteria, physicians’ biases and lack of awareness, logistical issues, and patient mistrust.
Parkland Health and Hospital System (PHHS) serves as the safety-net hospital for Dallas County. Parkland, in partnership with the University of Texas Southwestern, provides medical care to a large population that disproportionately includes underserved minorities. Cancer patients presenting to Parkland are typically diagnosed at a more advanced stage and are more likely to have had delays in their care.
Based on our previous observations, we believe that the greatest potential impact lies in addressing specific and modifiable aspects of patient care. We therefore propose a Breast Cancer Clinical Research Navigator with a role distinct from research coordinators that will focus on early identification of trial candidates, expediting initial patient evaluation, and improving provider awareness of trial options.
We believe that engaging a Breast Cancer Clinical Research Navigator in the ways outlined above, will result in early and integrated consideration and presentation of trial options and will impact both patient and clinician interest in clinical trials, thereby augmenting accrual.
2015 V Foundation Wine Celebration Vintner Grant in Honor of Rick and Elaine Jones With Support From Becky and Howard Young
Pancreatic cancer is an almost universally deadly disease because it spreads quickly to other organs (metastasizes) easily and there is no early detection mechanism. Surgery can be an effective treatment, but less than 10% of patients are diagnosed at a resectable stage. About 30% of patients with pancreatic cancer have locally advanced pancreatic cancer, where the cancer has not yet metastasized, but cannot be removed by surgery. The only way to kill locally advanced pancreatic cancer is with chemotherapy and radiation. Radiation therapy can kill any tumor but its therapeutic effects are limited by unavoidable damage to normal tissue near the cancerous target. For instance, adenocarcinomas of the pancreatic head require high doses of radiation to achieve tumor control, but these cannot be safely given to patient because the pancreas sits near a part of the small bowel called the duodenum, which is very sensitive to radiation damage. Thus, we can never give the amount of radiation needed to kill the tumor without causing undue harm to the duodenum (and the patient). My research will solve this problem by strengthening the duodenum and nearby tissues to withstand higher doses of radiation by activating the hypoxia-inducible factors (HIFs), which promote recovery from radiation treatments without protecting tumors. My published work has shown that HIF2 can reduce GI toxicity from radiation, and this proposal seeks to use this biology to make the duodenum more resistant to radiation toxicity to allow us to give higher doses of therapeutic radiation to the pancreatic tumors.
Ovarian cancer is a devastating disease heightened by its tendency to present when metastatic disease is already present. Many women diagnosed with the disease complain that despite their best surveillance efforts, the disease occurred completely “under the radar.” While most women are symptomatic at diagnosis, the symptoms are veiled as common inconveniences of daily life, such as bloating, fullness and pelvic discomfort. Primary treatment involves a combination of surgery and chemotherapy. Tumor control is achieved in >75%. However, despite these early treatment gains, a typical patient will suffer recurrence within 2 years, where limited curative options exist. These clinical observations have fueled the search for better treatment agents and strategies. The unprecedented explosion of information arising from analyses of the cancer cell environment has directed new investigative opportunities. One such observation in line with this clinical story is the efficacy of agents that target new blood vessel formation. Several clinical trials with these agents in both initial and recurrent disease settings have demonstrated benefit to women. However, improvement in survival has not been realized. Our investigation into why this might occur has uncovered that the immune system may be adversely contributing. Of great concern, though, is that this process appears to be induced by the very drug being used for therapy. The current proposal tackles this issue by specifically investigating and targeting these immune cells. Our clinical trial design uniquely identifies patients where this “escape” effect may be at work. The translationally-rich proposal holds promise to substantially improve treatment outcomes.
