According to estimates from the International Agency for Research on Cancer, worldwide, there were 18.1 million new cancer cases diagnosed with 9.6 million deaths in 2018. In other words, one in 5 men and one in 6 women experience cancer during their lifetime, and one in 8 men and one in 11 women die from the disease. As such, there is an urgent need for finding better treatments to reduce cancer-associated death. BRCA1 and BRCA2 are two genes that, when mutated, can cause cancer. Studies by many research groups have revealed critical roles of BRCA1 and BRCA2 in protecting our genetic material from damage caused by sunlight, radiation, and other environmental exposures. While BRCA mutations have been linked to a greatly increased risk of developing cancer, we do not yet fully understand the biological process of DNA repair mediated by the BRCA genes. This poses a challenge for patient counseling, determining prevention strategies, and the formulation of treatment plans when disease strikes. Here, we describe a research project to study BRCA1 and BRCA2 designed to fill this knowledge gap. The information and tools from our work will help explain why BRCA mutations cause disease and help formulate treatment regimens that are more effective than current ones.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Sarcomas are cancers of connective tissues in the human body. It affects children and teenagers more than adults. Cancers that spread to other parts of the body are difficult to treat and are not often curable. A new treatment approach called immunotherapy uses the body’s own immune system to fight cancer. Our approach uses immune cells of the body, namely T cells, to find and kill tumor cells after introducing an artificial molecule called chimeric antigen receptor (CAR). These CAR-enhanced T cells developed in our laboratory recognize a protein on the surface of the cancer cell, namely HER2. Patients with advanced sarcoma received these HER2-specific CAR T cells in our ongoing clinical trial. The CAR T cells did not cause severe adverse reactions in any of the treated patients. More than half of the 10 patients who received the cell treatment benefited from it, with 2 patients achieving tumor elimination and 4 others achieving cancer stabilization. We will now test if larger dose of T cells can be tolerated or increase the chances of benefit. We will also study immune responses in these patients to identify mechanisms, if any, that can lead to improved treatments. Finally, we will evaluate a new molecule that can help CAR T cells overcome tumor signals that turns them off. The insights gained from this study will help design and develop targeted treatments for sarcoma.
Peritoneal carcinomatosis (PC) — an aggressive metastasis of gastric cancer — is always fatal.
Approximately 20 percent of patients newly diagnosed with gastric cancer already have PC; and about 45 percent of those diagnosed will eventually develop PC. Researchers have a poor understanding of gastric cancer cells that populate the peritoneal cavity. Current therapies offer little help and research is limited. The lack of understanding of PC puts clinicians at a disadvantage when determining the best strategies for patients with this disease.
Researchers at The University of Texas MD Anderson Cancer Center are overcoming these obstacles through the Intraperitoneal Program. This program, which is led by Jaffer Ajani, M.D., professor of Gastrointestinal Medical Oncology at MD Anderson, is aiming to conduct high-quality multiplex profiling of PC cells and stroma (surrounding tissue). The program allows Dr. Ajani and his team to generate multiplex data for a large number of samples from patients and use innovative tools that, he believes, will result in transformative ways this disease is treated.
To carry out this research, Dr. Ajani’s team has already collected abdominal fluid from many patients with intraperitoneal metastases. From these samples, they have identified cancer stem cells, which they believe are responsible for spreading into the peritoneal cavity. Eventually, Dr. Ajani’s team aims to develop a deeper understanding of the immune biology of the peritoneal cavity and how cancer stem cells recruit normal cells to be protected from the immune system.
Too many lives have been lost to this cancer. In order to develop therapies that can be tested in preclinical models, researchers need to conduct a deep dive investigation into PC using multidimensional integrative analyses to comprehensively profile the tumor and its microenvironment. The goal of this work is to discover therapeutic targets, biomarkers and signatures with prognostic and predictive potentials, enabling us to build illuminating predictive models. The researchers’ ultimate mission is to use every resource available to find viable therapies to fight this terrible disease.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
While immunotherapy can sometimes result in dramatic and prolonged responses, it can also cause major toxicities. Immune-related adverse events (irAEs) are quite different than the toxicities seen with other cancer treatments, such as conventional chemotherapy. They occur when immunotherapy causes the patient’s own immune system to attack normal organs in the body. These toxicities may occur at any point in treatment, may be severe, and—of particular concern to cancer survivors—may be permanent.
irAEs remain poorly understood partly because immunotherapy research has focused almost exclusively on tumor biology, which is certainly relevant to immunotherapy effectiveness.However, we believe that toxicities irAEshave more to do with patients’ own immune systems.Our researchteam has expertise in cancer, immunology, and genetics. We have already collected clinical information and blood samples on hundreds of patients receiving cancer immunotherapy. With this information, we have identified some blood-based tests that may predict the future development of irAEs.
We now take this research to the next level by proposing genetic and functionaltests to identify underlying predisposition to irAEs. Specifically, we will study DNA and RNA in blood samples from our existing patient cohort. If successful, our research could ultimately help (1) identify high-risk patients, (2) customize therapy, (3) tailor monitoring, (4) expand immunotherapy use, and (5) prevent toxicities.
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.
“Spirit of Jimmy V” Award funded by the Dick Vitale Gala in honor of Chris Berman
Neuroblastoma is a fast-growing cancer that affects hundreds of infants and children in the U.S. each year. The age of the patient is one of the most important factors for survival. While infants diagnosed before the age of 18 months have a 95% cure rate, older children have only around 50% chance of survival. We aim to improve the treatment options against the more aggressive neuroblastomas in older children.
Recent studies show that a gene called SMARCA4 has a major role in these cancers. We are working to identify all the other genes that depend on SMARCA4 in diseased cells, and then attack the key weak spots. By targeting the whole network instead of a single gene, we will identify new ways to treat neuroblastoma in older children. Our research is a viable first step to improve survival and quality of life for children affected by neuroblastoma.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Gala
Children with liver cancers are hard to cure, if the tumor cannot be removed by surgery or has spread to distant organs. Current therapies cause significant toxicity and don’t work well against large tumors. These children need new approaches and immunotherapy may be a good solution. Immunotherapy relies on the body’s own infection and cancer fighting system.
A type of immunotherapy uses special white blood cells called T cells. T cells can be collected from patients and engineered with a molecule called chimeric antigen receptor or CAR. These CAR T cells can be infused back to patients to destroy the cancer cells.
We developed several versions of CARs which recognize glypican-3. This molecule is expressed in pediatric liver cancers. We systematically tested T cells expressing these CARs in preclinical models of liver cancer. We selected the CAR with the strongest antitumor activity. Now T cells expressing this CAR will be tested in a Phase 1 clinical trial in children.
With the help of the V Foundation, we will examine changes in the genetic programming of CAR T cells. We will evaluate the CAR T cell product, peripheral blood and biopsy samples. Our goal is to define the interaction between the CAR T cells and the tumor.
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.
Bladder cancer patients experience widely variable clinical outcomes. Some are cured of their disease with surgery alone, whereas others require chemotherapy, and only about half of individuals who receive chemotherapy benefit from it. These differences in clinical behavior are almost certainly based in differences in cancer biology, and the overall goal of our bladder cancer research program is to deeply define them so that optimal therapeutic approaches can be offered to each patient. We recently discovered that bladder cancers can be grouped into “intrinsic subtypes” that are remarkably similar to the ones that exist in breast cancers. One of the bladder cancer subtypes (“p53-like”) is similar to “luminal A” breast cancers, and like them, tend to be resistant to chemotherapy and metastasize to the bone. Their most distinguishing feature is that they contain large numbers of normal cells (termed “fibroblasts”) that are being implicated in drug resistance and bone metastasis in laboratory models of other types of cancer (including breast cancer). In this project we will examine further whether the p53-like tumors are chemo-resistant and metastatic to bone by analyzing several additional cohorts of patients treated with chemotherapy in clinical trials. Then we will directly examine the contributions of the fibroblasts to chemoresistance and bone metastasis in laboratory models. Our goal is to use the information to distinguish patients who will benefit from chemotherapy from those who will not. And by studying the biological mechanisms influenced by the fibroblasts, we should be able to identify new, more effective therapies for patients with chemoresistant bladder cancers.
The human immune response can not only eliminate infections caused by viruses, bacteria and fungi, but can also kill cancer cells. Immunity is mediated by white blood cells. Among the different types of white blood cells, killer T cells can eliminate cancer cells, whereas regulatory T cells and some types of macrophages can block anti-cancer immunity and actually support cancer growth. The ability of killer T cells to eradicate cancer cells can be blocked by “immune checkpoint” proteins within the tumor microenvironment. Drugs have been developed to inhibit immune checkpoints (CTLA-4, PD-1 and PD-L1); thereby releasing the “brakes” on killer T cells to fight cancer. Using a combination of immune checkpoint inhibitors more than half of patients with widespread melanoma can experience long-term remission and possible cure.
Unfortunately, immune checkpoint inhibitors have been largely unsuccessful in patients with advanced prostate cancer. To better understand why they are not more effective, Dr. Subudhi’s team has evaluated the immune profile of primary and metastatic prostate cancers. They have found that the bone metastatic site is a highly immunosuppressive environment. This likely accounts for the poor clinical responses seen in patients with metastatic prostate cancer treated with a single agent immune checkpoint inhibitor. The overall goal of Dr. Subudhi’s clinical trials program is to improve survival in patients with advanced prostate cancer by enhancing T cell functions while eradicating the immunosuppressive cells within the cancer. Ultimately, his aim is to make immunotherapies in prostate cancer as effective as they are in melanoma.
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