Funded in Collaboration with Stand Up To Cancer (SU2C)
Every cancer is unique pointing to the need for personalized medicine. In oncology, a fundamental challenge is to assign the right treatment to every patient due to cancers’ biological complexity and the lack of effective predictive biomarkers. At the Letai lab we developed a functional predictive assay called Dynamic BH3 Profiling to rapidly test different treatments prior to giving them to the patient. It has already been successfully proved as an excellent predictor in different types of cancer, including melanoma. We aim to combine sophisticated genomic analyses with this novel test to improve melanoma treatment, improving patients’ clinical outcome, clinical trials and drug development.
Hematopoietic stem cells (HSCs) are responsible for the lifelong regeneration of the blood and bone marrow. During the lifetime of an individual, genetic mutations can occur in HSCs that slightly alter their properties, potentially leading to diseases of excessive or deficient production of blood cells. When myeloid cells are chronically affected, these conditions fall into two main categories called myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). These disorders are the most common blood cancers in adults with ~20,000 new cases diagnosed each year in the United States. While these diseases themselves present significant problems such as excessive bleeding and more susceptibility to infections, in a significant number of these patients the disease transforms to a leukemia that is much more difficult to treat and rapidly proves fatal (typically about five months). It is important to identify the genetic processes associated with progression of MDS and MPN to leukemia to improve treatment of these patients. I believe we have identified a new pathway that facilitates this process by identifying a gene that is genetically mutated specifically in the leukemia phase of the disease, but not the preceding MPN phase. The goals of this work are to develop new models to understand these processes, and to identify factors to improve the treatment outcomes of such patients. As there are no effective therapies for these patients that progress to leukemia, any findings that improve the diagnosis and treatment of these patients would represent a significant advance in this field.
Triple negative breast cancer (TNBC) is aggressive and has a poor prognosis. Currently, chemotherapy is the only treatment option. Therefore there is unmet need to identify novel therapeutic targets for TNBC. Acquired resistance to targeted therapy, a newer treatment type with drugs targeting specific molecules necessary for tumor growth, poses another major clinical problem. We have recently identified a major mechanism that TNBC cells utilize to promote tumor growth. This proposal aims at deciphering this mechanism in cancer growth and drug resistance, as well as discovering novel therapeutic targets for TNBC.
Akt1, Akt2 and Akt3 are a “family” of proteins with both overlapping and unique functions. Akt plays critical roles in tumor growth, and a number of drugs targeting Akt are being tested in clinical trials. Our recent findings indicate that Akt3 has an increased expression in ~30% of TNBC. Importantly, Akt3, but not Akt1/2, is critical for regulating TNBC growth. Moreover, Akt3 is implicated in drug resistance to Akt inhibitors. We propose that Akt3 regulates tumor growth and resistance by activating specific downstream targets and upregulating receptors on cell surface. To identify novel Akt3 targets, we will use a discovery-based proteomics approach. For drug resistance study, we will analyze Akt3 signaling in tumor samples, and test if certain receptor inhibitors effectively eliminate resistant cells. In the short term, our results will provide rational combination treatment strategy to combat drug resistant breast tumors. In the long term, we anticipate developing effective therapeutics targeting Akt3 or its substrates to treat TNBC.
Prostate cancer is the second leading cause of cancer-related death in American men, resulting in 29,480 fatalities last year. Death from prostate cancer most frequently occurs following the development of resistance to first- or second-line androgen deprivation therapy (ADT). As such, there is a critical need to discover early drivers of ADT resistance to help guide selection of patients for earlier intensification of therapy.
The majority of cancer biomarker research has focused, to date, on protein-coding genes, which are pieces of DNA that are converted to RNA and then converted to protein. Our team instead focuses on investigating long noncoding RNAs (lncRNAs), which are pieces of DNA that are converted to RNA but are not further converted to protein. These lncRNAs, which function as RNAs instead of proteins, represent an underexplored, but crucial, area of cancer biology. Our team recently identified over 45,000 novel lncRNAs, and determined that several lncRNAs, including one named SChLAP1, were better indicators of disease progression than conventional protein-coding genes.
Based on our initial findings, we hypothesize that lncRNAs serve as important mediators of treatment resistance in prostate cancer. The goals of this application are: 1) to investigate the mechanism by which our top candidate lncRNA, SChLAP1, promotes ADT resistance and 2) to determine if SChLAP1 and other lncRNAs can serve as predictive biomarkers to guide therapy selection in patients with aggressive prostate cancer, using tumor samples from a phase III clinical trial.
