Archives: Grant

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.

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.

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.

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.

Funded in Collaboration with Stand Up To Cancer (SU2C)

Pancreatic ductal adenocarcinoma (PDAC) is a frequent cause of cancer death in the United States; it currently is the fourth most common cause of cancer death and is expected to become the second most common cause of cancer death within the next five years.  Unlike virtually all other major cancers, pancreas cancer is both increasing in incidence and has shown essentially no improvement in five year survival over the past two decades.   The exceptional lethality of pancreas cancer is multifactorial, resulting from an intrinsically aggressive biology, lack of effective means of early detection, and poor responsiveness to systemic chemotherapy. Clearly novel approaches to this disease are needed.

Although there have been anecdotal reports of responses to immune-based therapies in pancreas cancer, activation of cellular immunity using checkpoint inhibitors, vaccine strategies and transfer of genetically modified T cells has not been shown to be generally effective.  We have assembled a team of physicians, cancer immunobiologists, computational biophysicists, and engineers to better understand the unique immunological microenvironment of pancreatic cancer, develop the technologies needed to take advantage of therapeutic vulnerabilities, and to form a multi-institutional clinical consortium to readily implement these strategies to help change the course of this deadly disease.