New cancer drugs are needed to improve quality of care, deliver cures, extend life and prevent relapse. We need to hunt in new places or in places that are not yet fully explored to come up with ideas for better drugs. We have focused on a previously overlooked area that is prime for exploitation, namely how DNA is packaged into cancer cells. DNA is the instruction manual of the cell and must be copied forward when cancer cells divide, a process called DNA replication. However, because DNA is so long it must be packaged correctly into the cell nucleus after it is copied. The cell makes a large number of DNA-packing proteins called histones to accomplish this task. We aim to find ways to attack a cancer cell’s ability to make histone proteins as a new cancer treatment strategy. We expect this be safer (less toxic) than targeting DNA replication itself, and hope to find ways to target it specifically to cancer cells. To do this, we are focused on the details of the DNA packing problem, by digging into the cellular components that control this process and asking molecular questions using the latest technologies. We want to understand how this process works better and how it goes awry in cancer cells so that we can exploit our findings for new drugs.
Pancreatic cancer is the 3rd leading cause of cancer-related death in the United States, with a five-year survival rate of less than 9 percent. Activation of the immune response in the microenvironment is associated with better outcomes in pancreatic cancer patients. The tumor and gut microbiota has recently been shown to influence tumor progression by modulating the tumor microenvironment.
We have recently demonstrated that the composition of the gut microbiome may determine tumor behavior and outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. We have identified specific bacteria signatures in the tumors of long-term survivors (LTS) compared to the stage-matched- short-term survivors (STS). We have also shown that transplantation of fecal microbiome from LTS or healthy controls of pancreatic cancer patients into a mouse model of PDAC significantly reduces pancreatic cancer growth. These important findings prompted us to target tumor microbiome as a therapeutic approach in pancreatic cancer patients. Here, we propose to transplant stools from PDAC long term survivals or healthy controls into PDAC patient to change their immune suppressive behavior to immunoactivated one. To this end, we will first analyze the changes in microbiome of PDAC patients after the transplantation of gut microbiome from long term survivals or health controls. Next, we will evaluate the tissue obtained from biopsy and surgical specimen for the changes in tumor microbiome of PDAC patients. Finally, we will characterize the tumor immune infiltrates from tissues obtained from PDAC patients to see if we can switch PDAC immunosuppressive TME into immunoactivated by fecal microbial transplantation. This proposal would be the stepping stone to move forward efficacy trials in PDAC patients combining FMT with standard treatment or immunotherapy.
V Scholar Plus Award – extended funding for exceptional V Scholars
More than 40,000 American women die of breast cancer each year. One out of every eight women in the U.S. will develop invasive breast cancer during their lifetime. In 70% of these women, estrogen and estrogen receptor α (ERα) are key players in breast cancer diseases. Keeping this endocrine signaling function low by endocrine therapy is the best treatment right now. Yet, after 5 years, hormonal treatment stops working in more than 30% of these patients and the disease returns. Because hormone resistance is still a challenge, there are few effective therapies for these patients. We plan to study estrogen and ERα related to hormone resistance.
ERα binds DNA elements that regulate gene expression. These elements are very important in cancer development and progression. When these elements lose control, breast cancer becomes resistant to hormones. Thus, if we can find ways to understand and correct these elements in hormone resistant cells, we can find cures for ERα-positive breast cancers. The goal of this project is to understand how ERα controls DNA elements. We will identify markers to measure the presence and progression of breast cancer. Our research results may lead to new therapies that target this disease. Discoveries from this project may help with treating other cancers and may be useful for other research fields.
Immunotherapy has revolutionized cancer treatment. Immunotherapy drugs work with the immune system, which normally fights intruders such as viruses, to kill cancer cells. One approach involves taking down defenses set up by cancer cells to escape immune cells. Some tumors, such as kidney cancer, melanoma, and lung cancer, display on their surface a protein (PD-L1) that shuts off approaching killer immune cells. Drugs have been developed that mask PD-L1 allowing killer cells to dispose of cancer cells. Discoveries underlying these developments were recognized with a Nobel Prize in 2018.
However, not all tumors use the same defense mechanism. Here, we propose a novel strategy to identify patients most likely to benefit from drugs masking PD-L1. Up until now, most approaches have focused on evaluating PD-L1 on tumor biopsy samples. However, only one cancer site is sampled, few cells are evaluated, and the results are often unreliable.
We have developed a strategy adapting a radiology test, positron emission tomography (PET), and a PD-L1 masking drug, that allows us to evaluate PD-L1 across all tumor sites. In preliminary experiments, we show that we can label a PD-L1 masking drug so that it can be detected by PET. We then show, using patient tumors transplanted into mice, that we can identify tumors with high PD-L1.
Our goal is to evaluate immuno-PET (iPET) in patients in a clinical trial. If successful, iPET will better match patients to their immunotherapy drug, and identify patients unlikely to benefit and for whom other strategies should be developed.
Funded by the Kay Yow Cancer Fund
One of the greatest challenges in cancer treatment is that response to standard chemotherapy is frequently incomplete and fraught with adverse events. Current treatments are often ineffective because they function as a “one-size-fits-all” approach to a very diverse disease. This lack of success is magnified in triple negative breast cancer (TNBC), whose large and diverse group of subtypes greatly increases difficulty in treating a disease that makes up 15% of all breast cancers and disproportionately affects African American and Hispanic women. The goal of our project is to address these challenges by identifying and characterizing specific tumor vulnerabilities in TNBC to pave the way for novel combined chemotherapeutic treatments. By screening through each gene in the genome, we have found that TNBC cancers rely on a protein called SIK2 for their survival. We are working to understand why SIK2 is essential and to use inhibitors of SIK2 function to reduce TNBC tumor survival.
Liver cancer is among the top four causes of cancer death. Historically, liver cancer is driven by HCV. Now, liver cancer is the fastest-growing cause of cancer death in the United States. This is due to the increase of nonalcoholic fatty liver disease (NAFLD), affecting around 25% of the global population. Emerging evidence defines over-nutrition environment and circadian misalignment as risk factors for NAFLD and liver cancer. So far, there is no FDA-approved drug to target the progression of NAFLD to liver cancer. Therapeutic approaches for liver cancer are also limited. Therefore, it is important to understand the mechanisms behind NAFLD-related liver cancer and identify new therapeutic targets.
We reported that a lipid-lowering drug decreased liver fat more when given in the afternoon than when given in the morning. This work is an example of chrono-pharmacology, where giving drugs at specific times of the day can maximize efficacy. My recent work revealed eating time as a key pacemaker for rhythmic metabolic processes in the liver. We can find a potential preventive approach for metabolic disorders and cancer patients by exploring this relationship between the internal clock and eating time. Chrono-nutrition is adjusting diet schedules to maximize results for treatment. The future project will identify how circadian rhythm affects liver cancer cells. These studies aim to find new targets of circadian physiology and reveal insights into liver cancer prevention and treatment.
Funded by Lloyd Family Clinical Scholar Fund
The Epidermal Growth Factor Receptor (EGFR) gene mutations can be detected in about 15% of patients with lung cancers. In female lung cancer patients who have never smoked cigarettes, as many as 50% of patients have this EGFR mutation. These mutations in the EGFR gene can be different from patient to patient, but all lead to the generation of an active protein that drives cells to survive, proliferate, and become cancerous. Currently, we have efficacious drugs for some of the EGFR mutations, but many other mutations do not have an approved drug. To address this unmet need, I am leading a clinical and translational research program including multiple clinical trials aiming to bring new approvals to treat those atypical EGFR mutations lung cancers. We will collect clinical information and bio-samples (both blood and tissue) to understand why some tumors respond to a certain drug, whereas other tumors not, to characterize the landscape of resistance mechanisms for each group of EGFR mutations. We will test a number of novel drug-drug combinations to overcome resistance and provide more potential options for EGFR mutation lung cancer patients. In this program, we will take a team approach to engage investigators with different expertise, use leading-edge technologies, including computational biochemical approaches and single-cell transcriptomics analysis, and ultimately nominate future therapeutic options for patients.
The study will detect cancer of the prostate in African-American men. African American men develop prostate cancer at a young age. The cancer spreads rapidly making it difficult to treat. Our method will detect substances produced by prostate cancer. The test will examine blood collected from men who have concerns with their prostate. The study will develop the test and make it available in the clinic. The test will help African American men in the community who do not have access to medical care. Early finding of prostate cancer will provide enough time for cure and will help reduce cancer related suffering and death.
Renal medullary carcinoma (RMC) is a rare but deadly kidney cancer that mainly occurs in young individuals of African descent that carry a blood disorder called sickle cell trait. Most people carrying the sickle cell trait never develop any symptoms. Many do not even know that they have it. Approximately 1 in 14 African Americans have the sickle cell trait and are at risk for developing RMC at an average age of 28 years old. RMC is also an under-recognized global health challenge because the sickle cell trait is found in ~300 million individuals around the world, mainly in Africa. Almost every patient with RMC is diagnosed late, when the cancer has already spread to other organs. Less than 5% of these patients survive beyond 3 years. Furthermore, many patients with RMC are initially misdiagnosed and lose precious time while being treated with the wrong therapies. The chances of a cure considerably increase when RMC is diagnosed and treated early. With the help of our patient advocates, we have established the largest collection of blood and tissue samples from patients with RMC worldwide. Using these samples, we have found evidence that patients with RMC have antibodies against unique proteins found only in cancer. We have developed a novel technology that allows the detection of more than 400,000 of these antibodies using only a drop of blood, quickly (within 3 days) and affordably. Our proposal aims to investigate and develop this new approach for the early diagnosis of RMC.