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.
Lung cancer is the top cancer killer in the United States and worldwide, claiming over 1.5 million lives in 2012, according to the World Health Organization. The purpose of our research project is to understand how patients’ genetic ancestry contributes to the likelihood of acquiring specific harmful changes in DNA (“mutations”) in lung cells that lead to lung cancer. Mutations in the EGFR gene are important because EGFR mutations often cause lung cancer, especially in non-smokers. Significantly, patients whose lung cancers have EGFR mutations benefit from drugs targeting mutant EGFR, including gefitinib, erlotinib, and afatinib. Mutations in EGFR occur more frequently in lung cancer patients of East Asian or Latin American origin but the basis for this observation is a mystery, especially because these mutations are not inherited but arise after birth. Here, we propose to analyze DNA from 1500 Latin American lung cancer patients, to understand whether and how their genetic makeup leads to increased risk of developing EGFR-mutant lung cancer.
By defining the basis of increased risk of EGFR mutant lung cancer in Latin American populations, we could enable the use of effective existing treatments in this population. Additionally, if we can find a genetic marker for susceptibility to EGFR mutation, we could facilitate the screening, early detection and early EGFR-targeted therapy of lung cancer in at-risk populations. We therefore believe that our research plan could lead not only to an improved intellectual understanding of lung cancer but to improved outcomes for lung cancer patients from susceptible populations.
Mutations in the KRAS gene are one of the most frequent genetic alterations found in lung cancer, a disease that is associated with the highest cancer-related morality rate in the US. Despite their prevalence, we still do not have an effective therapeutic intervention to target lung cancers harboring KRAS mutations. In this application we will investigate novel approaches to inhibit the function of this protein in patient-derived (or ‘avatar’) models of lung cancer and then translate the most promising findings to early phase clinical trials.
Pancreatic cancer is a devastating disease. Current therapies for pancreatic cancer have modest effects as the 5-year overall survival is a discouraging 5-6%. One contributing factor to increased morbidity and mortality is cancer cachexia. Cachexia is defined as weight loss, muscle atrophy, fatigue, and weakness, in someone who is not actively trying to lose weight. Cachexia is a devastating condition affecting most cancer patients, but significantly more pronounced in patients with pancreatic cancer and is a significant therapeutic and personal dilemma. I have a significant background in clinical oncology with specialization in pancreatic cancer. The aims of my therapies are to improve and extend my patient’s quality of life. Unfortunately, our therapies can be premature or delayed primarily by the overall health of my patients. Premature in that we treat weak and malnourished patients that should not be given aggressive therapies for the risk of causing more harm than good. Delayed in that the patient is too weak and malnourished to receive any therapy and therefore will succumb earlier to their disease. With the expertise and passion of our collaborative group, we will investigate the possible biologic factors that contribute to pancreatic cancer cachexia. Our plan will be the future development of strategies to interfere with its deleterious effects on our patient population. In summary, we hope to improve the quantity of quality life in patients with pancreatic cancer.
The global burden of cancer, severe pathology bottlenecks in underserved regions, and evolving medical knowledge increase the need for inexpensive and rapid diagnostic approaches for point-of-care use. We developed a low-cost imaging module (D3), mountable onto standard smartphones, that exploits holography to detect and profile tumors using scant clinical samples. Cells are decorated with plastic beads coated with antibodies against various cancer markers. Recorded holograms (inherently noisy and undecipherable images) are transmitted wirelessly to a remote server via a secure, encrypted cloud service. Results are rapidly reconstructed and returned to the end user’s smartphone screen along with a diagnostic readout. Pilot testing of human biopsies demonstrated protein profiling capabilities comparable to gold standard methods and excellent diagnostic accuracies compared to expert pathology interpretation. To render the platform poised for global field testing, we propose to optimize D3 to achieve simultaneous, multiple marker testing along a spectrum of field conditions using scant samples. We will then inaugurate this next generation platform and pilot its global oncology reach by tackling a key unmet need – early breast cancer detection in Botswana. Testing for key markers in breast cancer specimens is universal practice in developed regions yet rarely performed elsewhere due to highly inadequate resources. Instead, empiric treatment with anti-estrogens occurs leading to over/under treatment and significant drug-drug interactions (e.g. reduced HIV medication levels). D3 could position itself as a key early detection tool in global regions, enabling judicious and personalized treatment and increased biological insight.
About 1 in 8 U.S. women will develop breast cancer over the course of her lifetime, and in the year of 2014, breast cancer has claimed the lives of approximately 40,000 women and men in the United States. Although initial remission can be achieved with chemo-treatments, the worry and fear of treatment resistance, recurrence, and death still have a deep impact on many breast cancer patients. It is recognized that cancer stem cells (CSCs), a long-lived, self-perpetuating cell population that can infinitely give rise to the bulk of a tumor as the “seed” of the cancer, account for cancer initiation, progression, chemoresistance, and recurrence. To date, treatment strategies designed to eliminate the genesis of the cancer (CSC) still remain a significant challenge. This project aims to identify critical cell components and their working mechanisms that are used to sustain the stemness of breast CSCs, and the identified mechanism will further be therapeutically targeted to direct CSCs to a differentiated cell (non-stem cell) fate, allowing breast tumors to become terminally dormant and sensitive towards chemotherapy. Our goal is to eradicate breast cancer in the next 10 years, and with the common stemness properties of CSCs between many cancer types, we believe that the applications generated from our research will continuingly contribute to overcoming the therapeutic hurdles of a broad spectrum of cancers and significantly benefit the cancer patient and the survivor community for decades.
Colorectal cancer is the second leading cause of cancer deaths in the United State, with African Americans having a significantly higher risk of developing colorectal cancer and of dying from colorectal cancer than do Caucasians. This study is based on the recent milestone publication from our team finding that 41% of colorectal cancers from African Americans are molecularly distinct from colorectal cancers from Caucasians, with African American colorectal cancers bearing mutations in certain genes that are never or rarely mutated in Caucasian colorectal cancers (dubbed: African American Colorectal Cancer, or AACC, genes). This proposal will examine whether AACC genes are similarly targeted for mutation in cancers from African Americans that live in different regions of the country; whether AACC gene mutations are associated with more aggressive colon cancer behavior; whether cancers with AACC gene mutations appear different under the microscope; whether AACC gene mutations show molecular footprints of exposures to environmental carcinogens; and whether mutations of AACC genes preferentially target genes that are inherited from African versus from Caucasian forebearers. We further will develop functional models for two AACC genes (EPHA6 and FLCN) that are mutated exclusively in African Americans and will test effects of these mutations on the ability of cancer cells to grow and to metastasize. We moreover will determine if the presence of these mutations turns on any signaling pathways whose activation would render these cancers sensitive to treatment with new types of anti-cancer drugs that are designed to target and shut down specific cancer-associated signaling pathways.
Acute lymphoblastic leukemia (ALL) is an aggressive cancer of the blood and a leading cause of disease-related death in children and adolescents. Cure rates of ALL have improved over the last decade thanks to innovative therapies, but it came at the cost of often severe toxicity associated with chemotherapy that can have long-lasting debilitating effects on children. The goal of our research is to move from the “sledgehammer” delivery of chemotherapy to “surgical precision” personalized ALL therapy, to minimize side effects and improve survival. We have recently discovered genetic factors (variations of our genetic make-up, DNA) that strongly influence the way thiopurine (an important anti-leukemic drug) is processed in patients, and we found that 80% of severe toxicity of this drug is due to genetic defects in two genes. Therefore, we reason that 1) patients should be tested for these DNA variations before ALL therapy starts, and 2) the genetic test results can be used to tailor chemotherapy for each patient to avoid toxicity, an approach also known as pharmacogenetics-based precision medicine. To achieve this goal, we have assembled an outstanding group of basic scientists and clinicians in 5 countries with diverse expertise, to preform comprehensive research in laboratory as well as clinical research in clinical trials of ALL. If funded, this work is likely to have immediate impact in the way we treat children and adults with ALL, demonstrating the importance genetics-guided precision medicine in cancer in general.
Rectal cancer affects 40,000 individuals in the US every year. The primary treatment is surgical resection when possible but a growing number of patients receive pre-operative chemo-radiation therapy before surgery to improve outcomes. In up to 30% of these patients, the tissue removed from the rectum after chemo-radiation is found to have no evidence of the original tumor. However, at present, the only accurate way to find out if the tumor responded completely to pre-operative chemo-radiation is to go through with surgery. There are no established biomarkers that can identify patients with complete response before surgery so that they may be potentially saved from a morbid operation. In previous work, we have shown that cancer mutations can be detected in blood plasma from advanced cancer patients. We have also shown that changes in the circulating levels of these mutations correlate with tumor burden. In this project, we are evaluating detection of cancer mutations in plasma from patients with rectal cancer as a potential biomarker. Our goal is to identify patients with rectal cancer whose tumors have completely receded after completing chemo-radiation before they under go surgery. These results will set the stage for prospective follow-up studies to enable biomarker-guided non-operative management of localized rectal cancers.
In spite of tremendous advances in the treatment of estrogen receptor-positive (ER+) breast cancer using therapies directed against the estrogen receptor (ER), patients frequently develop resistance to these therapies. These resistant tumors remain the most common cause of breast cancer death, yet mechanisms by which this resistance develops are poorly understood. Much more work is required to fully understand all of the clinically relevant resistance mechanisms in breast cancer patients treated with ER-directed therapies. Moreover, there is an urgent need to develop new therapies for patients who no longer respond to these therapies. The goal of this project is to improve our understanding of resistant ER+ breast cancer by using cutting-edge genomic technology to directly characterize tumor samples from patients who have developed resistant breast cancer, as well as systematic pre-clinical approaches in breast cancer cell lines. First, we will use next-generation sequencing technology to comprehensively characterize the genomic and molecular alterations from breast tumor samples obtained from 50 patients who have developed resistance to the drug fulvestrant, an FDA-approved therapy that directly targets the estrogen receptor. At the same time, we will conduct a systematic pre-clinical study in breast cancer cell lines to identify genes that might contribute to resistance to fulvestrant. Once completed, this work should help us understand how ER+ breast cancers develop resistance to ER-targeted therapies, as well as identify new targets and therapeutic strategies in resistant breast cancer.
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