TCRF
Funded Research

Breast cancer is the second leading cause of cancer-related death in women. Immunotherapies harness the body’s immune system to fight cancer, holding great promise to prevent recurrence and prolong survival. Immunotherapies have been less effective in patient’s with breast cancer in part, due to the recruitment of suppressive cells that prevent an anti-tumor effect. We will investigate strategies to decrease suppressive signals within the tumor, allowing anti-tumor signals to successfully eliminate tumor growth. We will also determine differences in suppressive signals between early versus metastatic breast cancers to improve response to immunotherapy for patients with all stages of disease.

Cisplatin-based chemotherapy has been widely used for treating a variety of solid tumors including breast, lung and ovarian cancers. Although initial therapeutic success is achieved, a number of tumors are found to be intrinsically resistant or gradually develop resistance to cisplatin treatment, which greatly limits its therapeutic potential. Notably, cisplatin belongs to the platinum compound family, which are known as the only heavy metal containing drugs used for chemotherapy. Our proposed research will focus on a growth-related signaling pathway, named the Hippo pathway in regulating heavy metal-induced stress response, which results in a unique mechanism accounting for the cisplatin-based chemo-resistance.

To identify circular RNAs abundantly expressed in Undifferentianted Pleiomorphic Sarcoma and illuminate how circRNAs catalyze cancer-promoting and drug-resisting conditions in the microenvironment surrounding tumor cells. In particular, we will study how circRNAs merge with RNAbinding proteins to powerfully modulate tumor cell secretions, which in turn forge a tumor-protective niche that renders many existing therapies ineffective against UPS. Finally, we will use newly developed molecular techniques to manipulate circRNAs in tumor cells, paving the way to design transcriptional therapies against UPS, and to use circRNAs to refashion the tumor microenvironment, rendering this intractable disease newly vulnerable to previously failed therapies.

Cellular immunotherapies, in which a patient’s immune system is genetically engineered to target cancer cells, are revolutionizing cancer treatment. However, these engineered cells do not always persist long-term in patients, which can lead to disease relapse. I propose that the DNA structure of these engineered immune cells changes over time, ultimately impairing the expression of receptors which target the cancer cells, and that these changes can lead to treatment failure. I will examine genetically engineered immune cells from patients receiving them for cancer treatment for this phenomenon, and correlate the DNA structural changes with engineered receptor expression and therapeutic response.

Clonal hematopoiesis describes a common pre-cancerous condition where blood stem cells gain mutations in cancer-associated genes that allow them to grow and expand abnormally. This condition occurs more frequently with increasing age and after chemotherapy for solid tumors where it is a strong risk factor for developing secondary blood cancers. Inflammation after chemotherapy exposure is known to favor proliferation of mutant blood stem cells. We are investigating the anti-inflammatory effects of metformin on mutant blood stem cell behavior and how the presence of clonal hematopoiesis impacts clinical outcomes in women who received curative-intent chemotherapy after surgery for advanced breast cancer.

For these patients, new treatments are being developed that recruit cells of the immune system to attack the cancer. To turn on these defenses, we need to deliver genetic instructions to about two hundred million immune cells, efficiently and safely. Unlike other strategies, these cells no longer need to come from the patients, who are already weakened. We have invented an engineering solution to do so and we are testing and optimizing it so that we can make this treatment widely available to patients and their doctors soon.

Bladder cancer continues to cause significant mortality in the US due to the lack of reliable methods to identify high-risk patients who benefit from chemotherapy. We propose a study to characterize cell-free circulating DNA in the plasma for the purpose of creating a new noninvasive biomarker to identify patients with high-risk of recurrence. First, we will perform whole genome bisulfite sequencing to compare the methylation signatures between the patients who developed recurrence and those who did not. The identified differential methylation loci will be refined and then validated in a separate group of patients.

Acute myeloid leukemia (AML) is a devastating blood cancer were blood producing stem cells are damaged and become abnormally functioning leukemic stem cells (LSCs). To date, there is still no curative treatment targeting these aggressive LSCs. We identified novel compounds that inhibit important growth mechanisms of LSCs. In AML animal models and patient samples, these compounds decrease AML and improve survival. We will use rigorous experimental approaches to better understand the mechanism how these novel compounds kill LSCs. This project has a high potential to develop a new class of drugs for precision AML therapy.

Immune checkpoint inhibitors had revolutionized cancer treatment. The most versatile such drugs are antibodies that target a receptor molecule called PD-1 or its ligand PD-L1. Although effective in many cancer types, response rates to these drugs rarely exceed 20-30%, necessitating the search for agents that synergize with PD-1/PD-L1 blockers. Using mouse models, we found that the conventional chemotherapeutic drug oxaliplatin has the unique ability to greatly enhance the response to PD-1/PD-L1 blocking antibodies. We will investigate how oxaliplatin increases the effectiveness of PD-1/PD-L1 blockers and will validate these findings in human lung cancer through a Phase I/II clinical study.

Multiple Myeloma is the second most common blood cancer. It arises out of plasma cells, whose normal function is to make antibodies to fight infections. Although in recent years the treatment has become more effective, it remains essentially incurable. One unique aspect of the disease is the close ties to the normal bone marrow cells, specifically the blood vessel cells. Without signals from these cells the cancer dies. We don’t know which signals are the most relevant; our experiments are designed to discover that. This could form the basis for new treatments designed to disrupt these pathways to benefit patients.

Sponsor: John Chute, MD