More than 70% of adults in the USA are obese or overweight. Obesity is a known risk factor for 13 types of cancer. This includes postmenopausal breast cancer. Breast cancer is the second most common cancer among women in the USA. It affects 1 in 8 women and leads to more than 40,000 deaths a year. Obesity is associated with a 30-50% increase in breast cancer incidence.
The expanded fat pad in obese patients surrounds breast cancer cells and supports cancer growth. However, we do not yet understand how the presence of breast cancer cells changes the surrounding fat pad, and how this, in turn, supports cancer growth. We propose that there is a reciprocal cross-talk between breast cancer cells and the cells of the surrounding fat pad, and that breast cancer cells secrete factors to generate tumor-supporting cells.
Our goal is to identify these secreted factors using functional studies and mass spectrometry approaches. We will investigate the underlying mechanism of how these factors change the fat pad. Finally, we will determine the functional importance of these changes to breast cancer cell growth. We envision that our discoveries will have a major impact on obese and overweight women at elevated risk of breast cancer. In the immediate future, our discoveries highlighting the dangerous cross-talk between breast cancer cells and the surrounding obese fat pad could lead to dietary interventions and weight-loss counseling. Long-term, we are excited by the possibility that our discoveries will lead to novel screening and therapeutic strategies.
Funded by the Stuart Scott Memorial Cancer Research Fund and the V Foundation Wine Celebration for Julie Maples, in honor of Antrese Rose Allegro
Breast cancer is one of the most diagnosed cancers in women and it is the top cause of cancer death in Black and Hispanic women. While great advances have been made in the detection and treatment of breast cancers, certain forms of breast cancer remain difficult to treat. Some patients develop resistance to current therapies leading to relapse, metastases, and ultimately death.
We are proposing to use our own immune cells to treat difficult cases of breast cancer. Our approach is to modify T cells with synthetic receptors to specifically recognize and kill breast cancer cells without harming normal tissues and organs.
We are using the T cells ability to patrol our body and modifying them to recognize specific molecular signals, such as the amount of a protein (HER2) present on the surface of cancer cells, to execute potent killing responses. If successful, our approach will lay the foundation for clinical studies, potentially will have major impact on our ability to treat effectively and safely some of the most difficult forms of breast cancer and will provide new approaches to other challenging solid cancers.
Adrenocortical carcinoma is a cancer of the adrenal glands that often kills the patient. Drugs to treat this cancer have failed because current research models, which use cell lines or mice, are too different from the cancer itself. Cell lines made from the cancer only have one type of cancer cell, while the original cancer has many types of cancer cells. Mice have many types of cancer cells, but the mouse cancer is too different from the human version to be helpful. To develop new treatments for this cancer, we need to make a model that includes many types of human cancer cells.
Organoids, or “mini-organs,” are a new research model that has many cell types and can be made from human tissues. They have been used to study other cancers that were previously difficult to study. We developed adrenocortical carcinoma organoids, which grew and made hormones just like the original cancer. Here, we use these organoids to study different types of cells in the cancer to determine which cells are more likely to cause worse disease. With this information, we can target weaknesses in the most dangerous cancer cells to stop the cancer from progressing, reduce treatment-related side effects, and improve survival and quality of life for patients with this terrible cancer. We also expect that our new methods can be used by scientists studying other cancers to figure out which cells are the most dangerous, so that patients with other cancers can benefit from this research.
Funded by the Stuart Scott Memorial Cancer Research Fund and the V Foundation Wine Celebration in honor of Leo Slattery, 2022 Volunteer Grant Honoree
A big part of the sequences that make our DNA come from viral infections that occurred in the past. These viral ‘fossils’ are typically not active to prevent damage to our genetic material, however in many diseases, including cancer, they are turned on. While it might be logical to think that the activation of these sequences would be a bad thing, evidence suggest that some of these viral fossils were repurposed to perform functions needed for a healthy life. In fact, some viral sequences participate in the formation of the placenta, in the way our genes are activated, and in the way our cells fight other viruses. Therefore, it is possible that the reason we see these viral fossils turned on in cancers is because they are helping the body fight the formation of tumors. Our goal is to test different ways by which the activation of these viral fossils could help prevent and fight cancer. To do this we will search for all the viral fossils present in our DNA, identify sequences that help our bodies find and destroy tumor cells, and test if one special viral fossil is able to prevent tumors by turning off its energy supply. We hope our findings can help the design of novel ways to treat cancer, taking advantage of the potential beneficial roles of these ancient viral sequences.
Small Cell Lung Cancer (SCLC) is a very aggressive form of lung cancer with few treatment options. This is due, in part, to an incomplete understanding of the ways by which this cancer develops. Recent genomic analyses have identified genes that are mutated and nonfunctional in SCLC indicating that they may play an important role. Interestingly, several of those genes encode for proteins that make up a large protein complex. The normal function of this complex is to manage how DNA is organized and packed inside the nucleus of a cell. We don’t know whether and how the inactivation of this complex promotes the development of SCLC. To address this question, we have developed new biological models in which the complex can either be inactivated or reactivated. Interestingly, we have found that blocking its normal function accelerates the development of SCLC. With the support of the V Foundation, we will assess how inactivation of the complex affects DNA organization and the expression of genes. We will also use the information we learn to find new strategies to eradicate these tumors. The proposed research will lead to a better understanding of the ways by which SCLC forms and may identify more effective treatments for patients diagnosed with SCLC.
Colorectal cancer is the second most deadly cancer worldwide. Both bacteria in our gut and the activity of our own cells in the intestines can contribute to the risk of colorectal cancer. However, we don’t know how these two factors work together to cause cancer. Some “bad” bacteria use toxins to cause colorectal cancer. But cancer takes over 1,000 times longer than bacteria’s lifespan to develop. So why do bacteria purposefully cause cancer? We think that “bad” bacteria remodel intestinal cell activity to produce nutrients that the bacteria can use as “food.” The rewired intestinal cell metabolism helps cancer cells grow faster. In other words, cancer development is a side effect of the “bad” bacteria trying to get food. If we can better understand this process, we can develop treatments that stop the growth of the “bad” bacteria and the tumors they cause. Using experiments in mice, we will first test whether the “food” produced by the cells in our gut helps the “bad” bacteria grow better. We will then try to block this process to reduce the growth of both the “bad” bacteria and the tumors. Lastly, we will test whether what we find in animals holds true in humans. This proposal is innovative because it uses what “bad” bacteria “eat” to help us understand how they cause cancer. We hope to use what we learn to develop better, more effective treatments for patients suffering from colorectal cancer caused by “bad” bacteria.
There are certain genes called “oncogenes” that when over expressed in cells can result in several deadly forms of cancers. Cancer patients with high oncogene levels show poor survival and have no defined cure. Therefore, there is an urgent clinical need for new therapies to treat these cancers. We are developing ways to selectively target oncogene-high cancer cells, while leaving normal cells unaffected.
DNA replication is important for cell survival. Our results suggest that oncogene-high cancers face many problems during DNA replication. These observations suggest that these cancers can be more dependent on pathways that allow them to fix the problems during DNA replication. Therefore, inhibiting these pathways will selectively kill oncogene-high cancer cells. In this grant, we will: (i) identify how oncogene-high cancers deal with problems in DNA replication and manage to survive; and (ii) identify why cancer cells with high oncogene levels do not respond to traditional cancer therapies. Our results can help find new ways to treat this high-risk group of patients who have little to no cure.
The role of the immune system is to survey the body in search of dangerous “non-self” elements and to eliminate them without damaging the host. Cancer is a disease which develops when host cells genetically change and begin growing in an uncontained fashion. It was therefore thought for many years that the immune system was incapable of recognizing or eliminating cancer cells due to their emergence from, and similarity to, “self” elements. The remarkable discovery that blocking signals (“immune checkpoints”) that restrain the ability of immune cells to recognize and destroy foreign elements can enable the immune system to treat cancer has fundamentally changed our approach to the treatment of these patients. Even in the setting of immune checkpoint inhibitors, however, immune cells lose functionality within tumors as part of a stepwise process known collectively as T-cell “exhaustion.” Reversing T-cell exhaustion is essential to make immunotherapy a viable treatment for all patients.
Our laboratory recently discovered that the metabolism of T-cells – the way that cells take up, break down, and utilize nutrients – becomes dysfunctional within tumors and, and moreover that this metabolic switch is required for T-cells to become fully exhausted. In work supported by the V foundation, we will understand how tumors exploit this metabolic dysfunction by creating metabolically inhospitable environments in which T-cells lose their capacity to control tumor growth. By identifying and reversing these environmental barriers, we hope to reverse or prevent T-cell exhaustion and make immunotherapy a viable strategy for every patient.
Invasive ovarian cancer is one of the deadliest types of cancer in the world, as less than 30% of these patients remain alive after 5 years. Treatment options are limited for these women, as they usually do not respond well to a new type of therapy that uses the patient’s own immune system to fight cancer. This is despite the fact that ovarian cancer does often have high numbers of T cells – an immune cell that has an ability to kill cancer cells. Therefore, identifying ways to improve the T cell’s ability to kill ovarian cancer cells will likely improve the outcome of these women. To this end, we have discovered a mutation in a molecule found in ovarian cancer cells that is associated with an improved outcome. Importantly, we have found the mutated version of this molecule is linked with increased T cell activity in ovarian cancer. Therefore, our study is designed to understand the connection between this molecule and immune cell activity. Our work will explain a new way that T cells in ovarian cancer can be stimulated to kill cancer cells and will improve our understanding of how immune activity is orchestrated in this disease. We expect that the completion of this work will drive the development of drugs that can target this molecule in cancer cells to improve responsiveness to ‘immune therapies’ and to significantly improve the outcome of women with ovarian cancer.
Pancreatic cancer remains a devastating diagnosis that is incurable in most patients, killing ~50,000 Americans per year. Treatment options including newer immunotherapy approaches are notoriously ineffective. These grim numbers motivate the search for a new strategy called “interception” that might prevent pancreatic cancer altogether. Interception seeks to target the earliest events in the progression of normal pancreas cells into invasive cancer. While this progression spans over a decade, no interception options currently exist.
We have identified a compelling target for interception. This protein is responsible for maintaining the normal identity of pancreas cells, and its activity diminishes as cells progress to cancer. Furthermore, studies comparing thousands of individuals with or without pancreatic cancer have found that this protein impacts risk of developing pancreatic cancer. Lastly, our team has developed potent drugs that can modulate the activity of this protein.
Our goal in this proposal is to pioneer an interception strategy by pharmacologically boosting activity of this protein to prevent progression of normal pancreas cells into cancer. We will characterize the mechanisms and impacts of these new drugs in mouse models of pancreatic cancer as well as in human specimens. Our studies will lay groundwork for clinical trials of interception to prevent pancreatic cancer altogether. Pancreatic cancer interception can also help address issues of psychological trauma associated with diagnosis and unequal access to treatment. Like taking aspirin to prevent heart disease before it happens, we envision these new drugs will be transformative in the fight to end pancreatic cancer.
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