V Scholar Archives - Page 36 of 59

Daniel Hochhauser, M.D., Ph.D.

Je Lee, Ph.D.

Pancreatic cancer is one of the most deadly diseases in the U.S. It is hard to diagnose early, and it does not respond to treatments when discovered late. Therefore, new methods for early diagnosis and prevention are critical. Currently, our approach to finding cancer biomarkers relies on technologies that lack spatial or temporal resolution for discriminating individual cells and tumor regions. In fact, much of our analyses are based on average measurements from the mixed population of different cell types within the tumor tissue. This means that each biomarker has to be validated in multiple experimental and pre-clinical settings through very time-consuming and expensive processes, severely hampering our ability to discover diagnostic or therapeutic biomarkers. We developed a novel method to image and sequence DNA and RNA genome-wide without extracting them from the tissue, and the nucleic acid sequence is visualized directly under the microscope. Therefore, we combine positional features associated with cancer progression and molecular or genetic features associated with cancer clonal evolution. Our proposal will determine genetic sequences associated with each pixel of cancer tissue images to generate a map of genetic alteration and biomarkers as a function of the tissue landscape. If successful, our proposal could signal a new approach to discovering genetic biomarkers using specific architectural hallmarks of cancer, rather than average gene expression differences between heterogeneous tissues.

Steven Barthel, Ph.D.

The precision oncology approach to the treatment of cancer bases treatment decisions on the biology of an individual’s cancer, most often using genetic alterations or mutations to inform therapy. This approach has been successful in a few cancer types, including lung cancer, melanoma, and chronic myelogenous leukemia where oral targeted therapies have led to both improved patient outcomes and fewer side effects compared to standard chemotherapy. However, this approach has not yet realized its full potential in these or other cancer types. In this proposal we plan to study new cancer-causing gene mutations involving the NTRK1, NTRK2 and NTRK3 genes, which are found in numerous types of cancer. We have already demonstrated that tumor cells treated with targeted therapies against this gene family can kill cancer cells in the laboratory. We have also observed early and dramatic tumor shrinkage in patients with different tumor types that share mutations in these NTRK genes. This proposal will focus on determining additional mutations of NTRK genes that may respond to therapy. The proposal will also study how cancer cells become resistant to targeted therapies and develop new laboratory models of NTRK+ cancer to develop new therapies for these cancers.

Christy Hagan, Ph.D.

Breast cancer is the most common cancer in women. Despite advances in understanding how breast cancer develops, this has not translated into better therapies. The majority of breast cancers are positive for hormone receptors, such as the estrogen and progesterone receptor (PR), and are dependent on these receptors and their hormone ligands (estrogen and progesterone) for growth. However, as tumors progress they become hormone-independent, meaning they grow in the absence of hormones normally required for cell growth, perhaps due to unregulated hormone receptors. It was recently shown that women who were taking hormone replacement therapy that included progesterone had an increased risk of developing breast cancer, underscoring the importance of studying PR in breast cancer. Understanding PR action in the context of breast cancer is important to the development of better therapies.

PR is required during normal breast development and pregnancy, activating genes in the nucleus that stimulate cell growth. Recently, we identified that PR also regulates genes that drive inflammation, a normal cellular process that can function uncontrollably in cancer, generating mutations that may drive cancer growth. Decreasing inflammation has been shown to reduce the risk of developing breast cancer. The objective of the proposed experiments is to determine how PR regulates genes involved in inflammation, and if PR-dependent inflammation can be detected, and eventually blocked, in breast cancer. Understanding how PR regulates inflammation could lead to the development of a new area of therapies for breast cancer, combining currently existing hormone-based therapies with treatment aimed at reducing inflammation.

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.