V Scholar Archives - Page 39 of 62

Amanda Lund, Ph.D.

If detected early melanoma is usually curable with surgery. However, melanomas are often detected at later stages after cancer cells have metastasized and survival rates for patients with metastatic disease are less than 15%. Furthermore, some thin melanomas, even when detected early, lead to mortality. What defines this difference in outcome is largely unknown and suggests a need for new markers that can predict a patient’s risk. Recently, the cellular microenvironment that surrounds a tumor has gained significant attention as a critical regulator of tumor progression, response to therapy and resistance. Effective therapies that specifically target immune suppression by tumor microenvironments have been developed; however, our understanding of the specific way in which these therapies work is incomplete. A better understanding of which parts of the microenvironment suppress immune responses will not only allow for better prediction of patient prognosis but may also help enhance a patient’s response to new immune-based therapies. Lymphatic vessel growth in melanoma is correlated with poor prognosis and enhanced metastasis to lymph nodes, however, until now lymphatic vessels were largely ignored as players in host anti-tumor immune responses. Our recent work demonstrates for the first time that lymphatic vessels are immune suppressive in tumor microenvironments and impair therapy. This proposal will test the hypothesis that lymphatic vessels directly contribute to immune suppression and suggests they may be a novel marker both for risk stratification in melanoma patients and as a novel therapeutic target.

Dustin Deming, M.D.

2015 V Foundation Wine Celebration Volunteer Grant in honor of

Will and Diane Hansen in memory of their daughter

Elizabeth Ann “Betsy” Hansen

Second year funded by UNICO, in honor of Steve Pisano

Colon cancer is the second leading cause of cancer related death in the United States. Despite an increase in colon cancer screening, many patients present with advanced disease, including a high proportion from minority and underserved populations. Improved treatment strategies are urgently needed to combat this disease. To develop new therapies, we are now examining what abnormalities or mutations are present in the DNA of the cancer cells. The mutations present in these cells are largely responsible for how the cancers act, including their response to certain drugs. We are now grouping colon cancers based on the profile of mutations that are present and developing combinations of drugs targeting each specific subtype.

In this proposal, we determine the ability of innovative treatments to target subtypes of colon cancer by taking advantage of the cell’s weaknesses based on the mutations they have acquired. Our laboratory has developed new cancer cell and mouse models engineered to develop colon cancers with certain mutations uniquely positioning us to accomplish the studies described in this proposal. These studies will bring us closer to the goal of personalizing treatment for patients with subtypes of colon cancer by identifying the patient population most likely to benefit. These investigations will also guide further studies into overcoming cancer cell drug resistance mechanisms with combination strategies and provide insight into the treatment of other cancer types possessing similar mutations.

Christine Lovly, Ph.D.

Funded by The Hearst Foundation

Important advances have been made in therapeutically targeting molecularly defined subsets of lung cancer that depend on specific molecular alterations for tumor growth. Prime examples include tumors which harbor EGFR mutations or ALK translocations. Many other potential “driver mutations” have also been identified in lung cancer, yet therapeutically actionable alterations are still only found in approximately 50% of lung adenocarcinomas. The principal objective of this proposal is to define a novel molecular cohort of lung cancer characterized by the presence of a previously unreported EGFR exon 18-25 kinase domain duplication (EGFRKDD). This novel EGFR alteration was initially detected in the lung tumor specimen from a young male never smoker with metastatic lung adenocarcinoma. In our preliminary data, we have also detected EGFR-KDD in the tumors from other patients with lung cancer as well as from patients with brain cancer. The proposed research uses in vitro and in vivo models as well as patient-derived tumor samples and clinical data to study EGFR-KDD. Findings from these studies could potentially be immediately relevant and provide a new avenue for precision medicine in these notoriously difficult-to-treat malignancies because there are already several approved EGFR inhibitors in clinical use

Andrew Hsieh, M.D.

Prostate cancer is the most common cancer among men in the developed world and there is currently no cure for its most deadly and advanced form, castration resistant prostate cancer (CRPC). The pervasiveness of this disease, particularly in minorities such as African Americans, highlights the importance of studying prostate cancer progression in order to develop effective new treatments. Historically, cancer research has focused on understanding how normal cells become cancer cells by accumulating alterations in DNA and RNA, the genetic material of a cell. However, these studies focus on only part of the overall process of gene expression, and neglect to take into account the ultimate end process of gene expression, protein production. Exciting discoveries from my lab and others have shown that the protein synthesis machinery is essential for cancer. This process can be hijacked by cancer, leading to grave consequences such as metastasis and drug resistance. Moreover, we have found that there is a remarkable therapeutic opportunity to drug cancerous protein synthesis without affecting normal cells in the body. The primary focus of our laboratory is to understand the fundamental connections between cancer and its protein making factories. We will employ a convergence of state-of-the-art genetic tools and genome-sequencing strategies to study how abnormal protein production leads to CRPC and drug resistance. Our studies will help identify patients whose cancers are addicted to aberrant protein synthesis and will accelerate the development and application of cancer therapies that target this poorly understood, but vital cellular process in cancer patients.

Luis Batista, Ph.D.

Funded by the Dick Vitale Gala with a gift from Derek and Christin Thompson in memory of Bryan Lindstrom

Bone marrow failure syndromes are a collection of disorders characterized by inadequate production of blood cell lineages from a common progenitor, the hematopoietic stem cell. Dyskeratosis congenita is an inherited bone marrow failure syndrome that comes to clinical attention during early childhood, and is associated with high rates of malignancy in children and young adults, with cancer being a major cause of death in patients. DNA sequencing efforts have established that dyskeratosis congenita has a clear genetic determinant, with patients carrying mutations in their DNA that affect the function of telomerase, a dedicated protein complex that is primarily responsible for maintaining the structure of our chromosomes.

Research regarding dyskeratosis congenita has been hampered by a lack of adequate models. In this proposal we are using genetically engineered human pluripotent stem cells to precisely determine the role that TERC, one of the main components of the telomerase complex, plays in bone marrow failure and cancer in children afflicted with dyskeratosis congenita. Using our innovative model, we will understand the importance of TERC for stem cell regulation and blood development. Recently we developed the technology to differentiate these stem cells in a controlled, quantitative fashion, to become any particular blood cell type present in the circulatory system. This allows us to reproduce the clinical effect of this disease, in a tissue culture dish, and therefore precisely understand the disease progression in dyskeratosis congenita. Our goal is to help delineate novel treatment strategies against dyskeratosis congenita, a condition that currently has no cure.

Kira Gritsman, M.D., Ph.D.

Acute myeloid leukemia (AML) is a devastating disease with poor survival. The standard treatments of chemotherapy and/or stem cell transplantation are not specific, and are toxic to blood cells, resulting in severe treatment-related complications for patients. Leukemias are composed of rapidly dividing “blast” cells, and the more rare “leukemic stem cells” (LSCs). These LSCs can lead to resistance and relapse, because they can evade chemotherapy. To achieve long-term remissions in AML and prevent relapse, we need to find more specific ways to kill LSCs.

The enzyme PI3 kinase (PI3K), which can modify proteins inside the cell, is more active in leukemic cells than in normal cells. However, PI3K is also important in normal blood cells. We identified a strategy to specifically kill leukemic cells by blocking specific components of PI3K called “isoforms”, which can sometimes substitute for each other in normal blood cells. We will determine whether this therapeutic strategy can also be used to kill LSCs.

Leukemic cells can also evade chemotherapy by hiding in their bone marrow microenvironment, the “niche”. Niche cells and leukemic cells “talk” to each other by sending signals back and forth, which can protect leukemic cells from chemotherapy. Cells need PI3K to process such signals. Inhibition of PI3K in niche cells could potentially kill leukemic cells by short-circuiting this crosstalk with the niche. We have found that PI3K in the niche cells is important for blood development. We will now examine whether inhibition of PI3K in the niche can compromise leukemic growth and progression.

Qing Zhang, Ph.D

Triple Negative Breast Cancer (TNBC) accounts for 15-25% of breast cancers. TNBC is well known for its aggressive clinical behavior and early peak of recurrence. Due to the lack of good therapeutic targets, TNBC represents the specific subtype of breast cancer with worst prognosis. Therefore, there remains the urgent question to be addressed: Can we identity important biological features that serve as high value targets for the development of novel treatment modalities for TNBC? This line of research carries significant social and economic importance. Hypoxia is a characteristic of solid tumor, which contributes to radiation and chemotherapy resistance. One important feature of tumor cells is that they sense the oxygen tension and rewire their signaling pathway to survive under harsh living conditions. EglN2 prolyl hydroxylase serves as an important oxygen sensor. In this proposal, we presented some preliminary data in the TNBC cell lines that getting rid of EglN2 could decrease TNBC tumor growth and invasion. We propose to obtain primary tumors from TNBC patients, implant them into mice and treat them with siRNA nanoparticles that deplete EglN2, which will be used to test the efficacy of targeting EglN2 in a patient relevant system. In addition, we will study mechanistically how EglN2 protein stability is regulated by FBW7 E3 ligase complex. Furthermore, we will implement a novel screening for EglN2 specific inhibitors, which will motivate testing the effect of these potential inhibitors on TNBC tumorigenesis. Successful completion of proposed research will open new therapeutic avenues in treating TNBC.

Cullen Taniguchi, M.D., Ph.D.

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.

Jose Trevino, M.D.

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.

Raymond Moellering, Ph.D.

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.