Jessie Villanueva, Ph.D.

The V Foundation MRA Young Investigator Award

Co-funded with The Melanoma Research Alliance

Although significant progress has been made treating melanoma and the recent approval of several drugs for the treatment of advanced disease, several challenges remain.  For example, clinical responses are generally short-lived as tumors quickly become drug resistant and patients relapse. Moreover, tumors can develop drug resistance through a diverse number of molecular mechanisms, making the development of second-line therapies extremely daunting.  Therefore, it is critical to identify therapeutic targets that are common to the majority of resistant tumors.  We have recently found that a protein kinase called S6K is activated in melanomas resistant to BRAF and MEK inhibitors.  Moreover, we showed that inhibition of this protein using a triple drug combination blocked the growth of resistant tumors.  This provides strong rationale for establishing S6K as a novel target for melanoma therapy.  Notably, S6K is a common node for most resistance pathways.  We propose to investigate the role of S6K in melanoma and determine the therapeutic value of targeting this protein.  Towards these goals we will determine the consequences of blocking S6K in melanoma, identify the proteins that are regulated by S6K and use this knowledge to delineate combinatorial approaches that can lead to long-term tumor remission in a large number of melanomas, including those resistant to BRAF and MEK inhibitors.  We expect that the data generated by these studies can be quickly translated into new strategies aimed at maximizing the therapeutic efficacy of MAPK inhibitors in melanoma and provide actionable information that will guide the design of future clinical trials. 

Qing Li, M.D., Ph.D.

Leukemia stem cells (LSCs) are able to regenerate leukemia after chemotherapy and cause leukemia relapses.  LSCs are transformed from the normal blood stem cells by mutations.  We found that one of the commonly found mutations NRAS is able to re-program the signaling pathways in normal blood stem cells and chamge them into LSCs.  Our studies showed that Nras does this through an unexpected pathway and targeting this pathway may lead to elimination of LSCs to potentially cure leukemia. 

University of Texas MD Anderson Cancer Center

Funded by the Kay Yow Cancer Fund

The overall goal of the University of Texas MD Anderson Cancer Center Ovarian SPORE is to prolong survival and to reduce the number of deaths from ovarian cancer through innovative research in the detection and treatment of ovarian cancer. The investigators funded by this grant have worked together to conduct five separate research projects. Project 1 has evaluated new biomarkers to create a blood test for early detection of ovarian cancer. When ovarian cancer is detected in stage I, up to 90% of women can be cured; however, only 20-25% of women are currently diagnosed at this stage. Detection of early stage disease in a larger number of women could improve the cure rate by 15–30%. Project 2 has tested drugs that can overcome the resistance that is developed to current therapy which targets the blood vessels that grow into and bring nutrients to ovarian cancer cells. Increasing the ability of drugs to eradicate the tumor blood supply will help kill the cancer cells. Project 3 has tested drugs for personalized therapy for low- grade cancer. Low-grade ovarian serous carcinoma is more common in younger women and it is a unique disease that is highly resistant to standard chemotherapy and difficult to manage. The goal of this project is to improve understanding of how low-grade ovarian cancer develops and progresses in order to identify new drug therapies that limit its growth. Project 4 has studied drugs for personalization of treatment for high grade ovarian cancers. Not all ovarian cancers will respond the same way or to the same extent to the chemotherapy drugs currently available or to the targeted therapies that are becoming the standard of care. This is due to molecular variation that exists from person to person and from cancer cell to cancer cell in the same patient. Finally, Project 5 has created modified cells that can be used to deliver a therapeutic agent directly to the ovarian tumors. Bone marrow-derived mesenchymal stem cells (MSC) are collected from an individual and modified in a test tube using recombinant DNA techniques. The modified cells are then injected into the patient and will move through the blood stream and ultimately integrate into the ovarian tumors. Once engrafted in the tumor, the modified MSC will produce a potent anti-tumor molecule which acts to reduce cancer cell growth.

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