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.
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
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.
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.
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.
