Shakeel Modak, M.D. & Brian Kushner, M.D.

Funded by the Dick Vitale Gala in memory of Eddie Livingston

Anti-GD2 monoclonal antibodies are now standard of care for patients with high-risk neuroblastoma, but there is little information on their biodistribution and tumor targeting in patients. We are developing a third generation anti-GD2 MoAb humanized 3F8 (hu3F8) for therapy of neuroblastoma. This proposed study will use a small dose of radioactive hu3F8 to determine its distribution and targeting using PET imaging which can provide sophisticated and quantitative data. This information will be critical in refining current dosing regimens for hu3F8 and improve the design of future clinical studies. Moreover, if specific tumor targeting can be demonstrated, as study of radioactive hu3F8 for therapy of patients with poor-prognosis neuroblastoma will be initiated.

Clare Yu, Ph.D. & Juliana “Julie” Wortman

Funded in Collaboration with Stand Up To Cancer (SU2C)

The goal of an exciting new form of immunotherapy is to get the immune system to kill cancer cells. When killer T cells arrive to kill tumor cells, some cancer cells are able to prevent this attack by inserting a protein that acts like a “key” (e.g., a PD1 ligand where ‘PD’ stands for Programmed Death) into a “keyhole” (e.g., a PD1 receptor) on the killer T cell.  Anti-PD1 immunotherapy drugs like nivolumab and pembrolizumab block the keyholes and prevent cancer cells from turning off the killer T cells. Such immunotherapy drugs are particularly effective when killer T cells have infiltrated the tumor. The goal of our project is to understand what features of the microenvironment of the tumor enhance the infiltration of killer T cells into the tumor. The tumor microenvironment, which includes cells, protein structures (like collagen fibers) made by some of these cells, blood vessels, and lymph vessels, typically provides a supporting environment for the tumor to grow. However, changes to the tumor microenvironment can inhibit the growth of the tumor and even lead to its demise. We will carefully characterize the spatial arrangements of the different types of cells and structures in the breast cancer tumor microenvironment in an effort to determine what enhances infiltration by killer T cells. Knowing this could lead to more effective immunotherapy.

Herbert Levine, Ph.D. & Xuefei Li, Ph.D.

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.

Steven Altschuler, Ph.D. & Xiaoxiao Sun, Ph.D.

Funded in Collaboration With Stand Up To Cancer (SU2C)

One of the foremost challenges to cancer treatment is the emergence of drug resistance.  Adding complexity to this problem is the realization that both the initial as well as the emergent drug-resistant cancer population can be in highly heterogeneous epigenetic and genetic states and from populations of very different sizes.  This heterogeneity makes it difficult to predict which cells will survive drug treatment and which drug-resistance mechanism will emerge, repopulate the cancer cell population and ultimately cause relapse.  Our goal is to better understand which cellular subpopulations are predisposed to initially survive targeted therapy, how diverse these subpopulations are from one another, and combination therapies would best target these subpopulations.  To accomplish this, we will make use of novel high-throughput assays for drug treatment, genomic and image analysis and mathematical analysis of cellular heterogenity and evolution.  These studies will address questions that are central to the fields of cancer biology, modeling, and cancer therapeutics, and allow us to test novel therapeutic approaches that can then be rapidly translated to the clinical context.

Victor van Berkel, M.D., Ph.D.

Funded by the Louisville Friends of V

Lung cancer is responsible for more cancer deaths each year than breast, colon, and prostate cancer combined. Part of the problem resides in the lack of symptoms associated with lung cancer – many patients already have advanced disease on presentation. Currently, the best method for identifying lung cancer involves computed tomography (CT scans) of the chest; while this has been demonstrated to improve cancer mortality by identifying earlier stage cancers, it also identifies multiple nodules within the lungs that are not malignant. In an effort to more precisely diagnose early stage lung cancer in at risk individuals, our group has turned to breath analysis. Human breath contains thousands of compounds from atomic hydrogen to complex biological molecules. Recently a class of organic compounds known as carbonyls have been associated with lung cancer.   Our research group has devised a simple method to extract and measure these compounds from a single breath.  We have identified four specific cancer markers among these compounds – the chance of having cancer increases with the number of elevated cancer markers identified in the patient’s breath.  The proposed project seeks to determine if breath analysis is as effective as CT scan in screening for lung cancer by comparing the two methods in the same patients. We will also study patients after a cancer has been resected to determine if recurrence of cancer can be effectively detected by breath analysis relative to CT scanning.

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.




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

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.

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.

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.

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