New York Archives - Page 9 of 12

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.

Jedd Wolchok, M.D., Ph.D. & John Moral, M.D.

Funded in Collaboration With

Stand Up To Cancer (SU2C)

Pancreatic cancer is a lethal disease. 95% of patients die within 5 years of diagnosis, despite our best current treatments including surgery, chemotherapy, and radiation. By 2020, pancreatic cancer is projected to become the second leading cause of cancer death in the United States. Novel strategies to combat this deadly disease are urgently needed.

T-cells are highly specialized cells of the immune system designed to protect the human body from infections and cancer. In the past decade, we have discovered that T-cells recognize proteins that only cancers make, identifying cancers as foreign, triggering T-cells to kill cancers. Cancers however are equipped with strategies to escape T-cells. Our group has recently identified a drug paricalcitol that eliminates barriers that tumors have developed to block T-cell attack. Our preliminary findings demonstrate that this drug increases T-cell numbers within tumors by greater than 10 fold. These results are promising as it allows us to further boost T-cells with other drugs, and increase the ability of T-cells to kill tumors.

Our proposed research will delve deep into understanding the specific proteins on tumors that T-cell recognize, the specifics of how tumors create barriers to block T-cells, and combining paricalcitol with other drugs that boost T-cells in a clinical trial. Our proposals allow us to gain a deeper understanding of the biology of T-cells in pancreatic tumors so that we may develop better treatments to improve outcomes in patients.

Piro Lito, M.D., Ph.D.

Mutations in the KRAS gene are one of the most frequent genetic alterations found in lung cancer, a disease that is associated with the highest cancer-related morality rate in the US. Despite their prevalence, we still do not have an effective therapeutic intervention to target lung cancers harboring KRAS mutations. In this application we will investigate novel approaches to inhibit the function of this protein in patient-derived (or ‘avatar’) models of lung cancer and then translate the most promising findings to early phase clinical trials.

Michael Walsh, M.D.

Funded by the Dick Vitale Gala

The advent of molecular biology and molecular profiling in clinical medicine has transformed our understanding of childhood leukemia. As a result, we are now empowered to shift away from the classification of hematologic malignancy based on microscopic appearance towards a new paradigm of diagnosis and treatment focused on specific molecular mechanisms of pathogenesis, or alterations detected in both leukemia cells and cells representing an individual’s heritable constitution. The heritable, constitutional or germ-line contribution to the development of childhood leukemia is a phenomenon increasingly recognized in childhood cancer. Studies to date have revealed the constitutional basis for cancers in subtypes of leukemia, however there is a clear missing heritability fraction given a high frequency of families without an identifiable genetic etiology. Given a lack of awareness and an incomplete germline evaluation, pediatric oncologists are unable to take avail of complete information pertaining to a child’s predisposition to developing leukemia when planning therapeutics and guiding. Knowledge of germ line alterations may direct patient care, and enable genetic counseling for patients and their families. My research focuses on identifying the heritable underpinnings of childhood leukemia.

Richard Possemato, Ph.D.

Funded by Hooters of America, LLC

Cells within a tumor must acquire nutrients from their environment and convert these nutrients into the cellular components necessary to support continued growth. This set of processes is broadly referred to as tumor metabolism. We are interested in understanding how tumor metabolism is distinct from the metabolism of normal tissues with the hope of identifying those genes or pathways upon which cancer cells are particularly dependent for survival. Recently, we have become fascinated by how tumors utilize one key metabolite, the amino acid serine. We found that the production of serine is activated in several cancer types, including breast cancer of the basal type, a particularly difficult to treat form of breast cancer. Cancer cells use this serine for various purposes, including the production of DNA. In this proposal we will evaluate the anti-cancer effect of inhibiting utilization of serine in a mouse model of basal breast cancer that recapitulates many aspects of the human disease. Furthermore, we will use a novel technology permitting editing of the cancer genome to determine whether perturbing serine utilization uncovers additional dependencies which can be the target of future anti-cancer therapies.

Andrea Schietinger, Ph.D.

Cancer cells express mutated proteins that are distinct from the proteins in non-cancerous cells, known as “tumor-specific antigens.” Over a century ago, scientists reasoned that our immune system (T cells) should be able to recognize these mutated proteins as “foreign” and eliminate cancer cells. While we find tumor-specific T cells within tumors, these T cells are not functional, allowing cancers to grow unimpeded. Our goal is to understand why tumor-specific T cells are dysfunctional and develop strategies to reprogram these tumor-specific T cells to fight cancer.

Using genetic cancer mouse models, we found that during tumor development, tumor-specific T cells become dysfunctional because the genes and pathways needed for normal T cell function are dysregulated. All cells in our body, including T cells, contain two layers of information encoding each cell’s characteristics. The first layer is the genome and consists of the DNA nucleotide sequence, the second layer is the epigenome and consists of chemical modifications to DNA or to the scaffold proteins associated with DNA. The genome and the epigenome together determine a T cell’s properties. Because functional and non-functional T cells in our model have identical genomes, tumor-induced loss of function must result from epigenomic changes. We propose to define the epigenome modifications that render tumor-specific T cells non-functional and test strategies to reverse this “code of dysfunction” so that we can reprogram tumor-specific T cells for human cancer therapy.

Ross Levine, M.D., Friederike Pastore, M.D.

Funded in Collaboration with Stand Up To Cancer (SU2C)

Preclinical and clinical studies have informed the development of increasingly effective cancer therapies that can lead to dramatic clinical responses. However, in the majority of cases, patients subsequently develop therapeutic resistance. Although recent studies by our labs and by others have elucidated mechanisms of resistance, the complex series of genetic and epigenetic events that drive therapeutic resistance have not been well delineated, there are few therapeutic options to prevent resistance. We have chosen acute myeloid leukemia (AML) to investigate the dynamics of therapeutic response and resistance for several important reasons. First, there is abundant evidence that targeted therapies (tyrosine kinase inhibitors) can induce substantive clinical responses, including complete remissions, in patients with genotypically defined disease subsets. Moreover, combination chemotherapy can induce a high rate of complete response similar to that observed with molecularly targeted therapies. Second, our team proposes to perform genomic and transcriptional/epigenomic studies of serially obtained clinical isolates from patients before therapy, at the time of maximal response, and at therapeutic relapse. Our clinical sites have established a robust infrastructure to obtain clinical samples at the different time points. This sampling approach, coupled with state-of-the-art genomic, transcriptional, and functional studies, will address questions that are central to the fields of cancer biology, modeling, and cancer therapeutics, and – most importantly will allow us to test models of the evolution of drug resistance and novel therapeutic approaches that can then be rapidly translated to the clinical context.

Gurinder Atwal, Ph.D. & Raditya Utama, Ph.D.

Funded in Collaboration With

Stand Up To Cancer (SU2C)

Tumors consist not only of cancer cells, but also stromal and immune cells that constitute the tumor microenvironment (TME). Cancer cells can take on dramatically different properties based on the microenvironment. The clinical impact of the TME is only becoming appreciated in recent years. In many different cancer types, including breast cancer (BC), tumors with higher stromal fractions portend worse clinical outcomes. In contrast, tumors infiltrated by CD8 T cells have better clinical outcomes. Hence, tumors behave differently based on the collective behavior of the microenvironment. We will leverage biotechnology advances in sequencing single cells to better understand the important determinants of the coevolution between the adaptive immune response and the tumor. By tracking the spatial geometry of cells in tumor samples we hope to better understand the TME and ultimately determine which genetic factors can be best exploited for therapeutic intervention.

Jose Baselga, M.D., Ph.D. & Guotai Xu, Ph.D.

Funded in Collaboration With Stand Up To Cancer (SU2C)

The so called targeted therapies are effective in tumors that strictly depend on a given protein or cellular signaling (the target) for growth and survival. Hyperactivation of the PI3K pathway is frequent in breast cancers and its pharmacologic inhibition showed clinical responses. However, these molecules alone cannot elicit a durable inhibition of tumor growth because the tumor can adapt and compensate the inhibition of the pathway.

Thus, targeting these compensatory mechanisms in combination with the PI3K pathway would in principle lead to stronger and more durable antitumor activity.

In this proposal we aim to validate in the laboratory theoretical predictions of successful drug combinations. These predictions are obtained from mathematical models developed from what is currently known about the perturbations of the PI3K/AKT signaling network in response to different inhibitors of the pathway. In addition, we plan to test therapeutic combinations based on genomic analyses from tissue samples of breast cancer patients treated with PI3K inhibitors.

Taken together, our results should provide the rationale to test novel and more effective therapeutic options for patients with hyperactivation of the PI3K pathway.

Benjamin Greenbaum, Ph.D. & Alexander “Sasha” Solovyov, Ph.D.

Funded in Collaboration With Stand Up To Cancer (SU2C)

The study encompasses multiple directions. First, genome of cancer cells acquires mutations at a higher rate compared to benign cells. Some of these novel mutations affect proteins synthesized within the cell, and these modified proteins (tumor neoantigens) may interact with immune system. We identify these novel neoantigens and study their interaction with immune cells in the tumor microenvironment. The other direction is quantification of non-coding RNAs, in particular, some repeat RNAs, expressed by cancer cells. We focus on the mechanisms of expression of these RNAs, their immunogenic properties and their interaction with tumor microenvironment. Understanding these topics would open the door towards unleashing immune response against pancreatic tumors.