Small Cell Lung Cancer (SCLC) is a very aggressive form of lung cancer with few treatment options. This is due, in part, to an incomplete understanding of the ways by which this cancer develops. Recent genomic analyses have identified genes that are mutated and nonfunctional in SCLC indicating that they may play an important role. Interestingly, several of those genes encode for proteins that make up a large protein complex. The normal function of this complex is to manage how DNA is organized and packed inside the nucleus of a cell. We don’t know whether and how the inactivation of this complex promotes the development of SCLC. To address this question, we have developed new biological models in which the complex can either be inactivated or reactivated. Interestingly, we have found that blocking its normal function accelerates the development of SCLC. With the support of the V Foundation, we will assess how inactivation of the complex affects DNA organization and the expression of genes. We will also use the information we learn to find new strategies to eradicate these tumors. The proposed research will lead to a better understanding of the ways by which SCLC forms and may identify more effective treatments for patients diagnosed with SCLC.
One of the biggest advances in cancer therapy in the past century has been the recognition that the immune system can be targeted by drugs to trigger immunity against tumors. These drugs, called ‘immunotherapies’ have improved survival for patients in a large and growing number of cancers. However, across cancer types, most patients do not durably benefit from treatment. The reasons for this lack of benefit in particular tumor types and patient populations are unclear. We have developed an approach that leverages new technologies that give us insight into the states and activities of individual tumor and immune cells directly isolated from patient tumors. This approach allows us to dissect mechanisms of resistance to immunotherapy and cellular responses to novel treatments. We are applying our strategy in head and neck cancers, an under‐studied class of tumors that is diagnosed in more than 60,000 people in the US each year. Our preliminary studies have identified distinct immune suppressive pathways enriched in head and neck cancer. In the present project we will test whether drugs aimed at targeting these pathways can restore the anti‐tumor activation of immune cells. If successful, these studies aim to: i) validate the use of novel combination immunotherapies for head and neck cancer and ii) identify biomarkers of response that will allow us to select the patients who will most benefit from these combinations.
Funded by the Stuart Scott Memorial Cancer Research Fund
Pancreatic cancer is a deadly disease. Most patients with pancreatic cancer are diagnosed at late stages. There are no impactful treatments for this disease. Patients with advanced disease only survive for a few months. There is a need for novel approaches for novel therapies. We need to understand the biology that allows cancer cells to create new tumors and invade other tissues. We propose to study the role of a new RNA modification. These changes on RNA control many aspects of the cells. Recently, the proteins that modify the RNA have been involved in several cancer types. However, the way that they act in cancer cells is unknown. We propose that the RNA changes are used by cancer cells to increase their ability to grow and invade new tissues. Thus, we propose to use multiple approaches to test the role of this RNA modification in pancreatic cancer initiation and progression. Understanding the basic mechanisms involved in the abnormal use of this RNA changes could lead to the development of novel therapies to treat cancer and metastatic diseases.
First year of this grant was funded in part by UNICO, in memory of Carl Esposito
Lung cancer is the leading cause of cancer deaths worldwide in men and women, with adenocarcinoma being the most prevalent subtype of non-cell lung cancer in the US. The National Cancer Institute estimates that, in 2016 alone, over 220,000 Americans were diagnosed with lung cancer and close to 160,000 Americans died of their disease. These dismal numbers have not changed significantly over the past decade. Thus, despite enormous advances in our understanding of many of the genetic, epigenetic, and immune events that underlie lung cancer development, a vast amount of knowledge remains to be amassed in order to improve human health. The experiments outlined in this proposal aim to elucidate how an understudied class of genes, called long noncoding RNAs (lncRNAs), participates in lung cancer development and may be harnessed for therapeutic applications. Specifically, we propose innovative approaches to investigate a set of lncRNAs downstream of the key tumor suppressor protein p53. By selecting this pathway, our intent is to dissect a molecular network, which represents a known barrier to lung adenocarcinoma progression, allowing us to discover and characterize lncRNAs that may modulate the transition to advanced and metastatic disease. Our ultimate goal is two-fold – first, to open new avenues in how we explore the significance of lncRNAs in disease states, such as lung cancer, for which few effective treatment options exist, and second, to make the first strides towards deciphering the regulatory code of lncRNAs, thus expanding the druggable space in cancer and ultimately improving patient outcomes.
Funded by the Dick Vitale Gala in memory of John Saunders
My research team is developing and applying novel tools for genetics, genomics and systems biology to tackle fundamental problems in cancer biology and therapeutics. In this project, we will focus on childhood cancer, the leading disease-related cause of death among children in the United States. Better treatments for these types of cancer will thus deeply benefit children. Developing such treatments will require addressing the highly complex and heterogeneous nature of cancer, for any given tumor can contain an enormous repertoire of genetic mutations within it that can also change over time. Understanding the roles of cancer genes has been hampered by the lack of large-scale methods to directly identify and interrogate the function of large numbers of genes in vivo. My goal is to invent such a platform, which will allow simultaneous mapping of the effects of many genes on cancer progression and therapeutic responses. The platform will combine genome editing, synthetic biology, in vivo animal models, high-throughput genetic screening and high-performance computing. I will develop this platform and apply it to study both solid tumors and liquid cancers diagnosed in children. I will first use it to perform large-scale in vivo genetic analysis in medulloblastoma to reveal the global genetic landscape of the progression of this disease. This analysis will also discover important driver genes, providing knowledge for more precise diagnostics and prognoses, and potentially better therapeutic strategies. Discovery of such targets will ultimately lead to improved therapeutics to save many children’s lives from childhood cancer.