Grant Archive - Page 64 of 138

Donita Brady, Ph.D.

Funded by the Stuart Scott Memorial Cancer Research Fund

Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal cancer with a five-year patient survival rate of fewer than eight percent. This dismal statistic is caused in part by the inability to detect PDAC early enough for surgical resection and PDAC tumors do not respond to standard chemotherapies. Ninety-five percent of PDAC tumors have an activating mutation in the gene KRAS. Despite 30 years of research invested in anti-RAS therapies, it is still not possible to directly inhibit RAS clinically. Hence, research has focused on identifying cellular processes that help KRAS mutant cancers grow, survive, and resist treatment with chemotherapies. One cellular process that mutant KRAS turns on in PDAC is autophagy, which is a process of ‘self-eating’ in which cells digest themselves in order to recycle building blocks needed as fuel sources for aggressive growth. Chloroquine, a drug that blocks autophagy, reduces PDAC tumor growth in preclinical models and clinical trials. In addition, the tumor-inhibiting effects of gemcitabine, a frontline chemotherapeutic for advanced PDAC, are enhanced when autophagy is decreased with chloroquine. However, chloroquine blocks autophagy non-selectively, requires high doses, and turns on autophagy when treatment is prolonged. Therefore, alternative autophagy inhibitors are needed. Recent studies in our lab discovered that limiting the availability of the transition metal copper to KRAS mutant cells reduces autophagy and in turn tumorigenic properties. Thus, the proposed studies will address whether copper-reducing drugs used to lower copper levels in humans can be repurposed for the treatment of KRAS mutation-positive PDAC by blocking autophagy.

Andrea Bonetto, Ph.D.

People that get cancer usually take medicines, called “chemotherapy”, that often made them feel very tired and sick. These problems can last for many months, even after they are completely cured.  In our laboratory we demonstrated that animals that take chemotherapy lose weight and are weaker. As of now, we do not know how to prevent this, in particular because we do not know the causes. For this reason, we want to learn why patients with cancer show the signs of fatigue, so that we can also find new medications to improve their health and help them feel better. Very recently, we discovered that the medications used to kill cancer also destroy the “mitochondria”, that are the little engines in the cells, in our muscles. Because of this, we think that if we can prevent the mitochondria from being lost then we can also help the patients feel better and less tired.  We plan to give mice with cancer the regular medications, with or without a new drug, called MitoQ. We think MitoQ will protect the mitochondria in the muscle of mice, will prevent them from losing weight and will make them feel stronger.  If we our idea is correct, in the future we will propose the use of MitoQ also in people with cancer. By doing so, the patients will feel better, will have fewer troubles due to the chemotherapy and will also have a better chance to get completely cured and go back to a normal life.

Ewelina Bolcun-Filas, Ph.D.

Funded in partership with WWE in honor of Connor’s Cure

Young girls who survive cancer may also face the devastating prospect of reduced fertility and hormonal problems when they reach adulthood. Treatment of pediatric cancer damages ovaries and lifetime egg supplies in up to 20% of young girls. Current strategies to correct loss of fertility involve removal of eggs from patients prior to treatment, but this is invasive and does not prevent the chronic health problems that result from ovarian damage.

To improve quality of life for young female cancer survivors, we must develop strategies to protect their egg supplies, which are critical for continuous endocrine function of ovaries and fertility. Our goal is to identify egg-saving treatments that can be used along with standard cancer therapies.

We will begin by analyzing how eggs and other cells in the ovary respond to different cancer treatments. By detecting changes in the levels of proteins in response to various cancer therapies, we can learn which proteins are responsible for egg death and identify drugs that target those proteins to prevent eggs from dying.

Our lab has previously found that a specific protein, CHK2, promotes elimination of eggs in response to the kind of damage caused by cancer treatments, making this a promising target. We will test the feasibility of targeting CHK2, and we expect that our work will demonstrate the benefits and potential risks of CHK2-targeting drugs for protecting eggs. We also expect to provide a list of novel drug targets for egg protection in cancer patients.

Michael Birnbaum, Ph.D.

Scientists have recently made tremendous progress in treating cancers by activating the immune system to attack the tumor. However, these therapies are not effective against cancers with less DNA damage due to insufficient anti-tumor immune responses. The immune system is capable of attacking these tumors, but suppressive immune subtypes such as regulatory T cells (Tregs) are coopted by the tumor to protect itself. Tregs are associated with poor survival in many cancers, and show enrichment for particular T cell receptors (TCR). The TCR senses targets by binding to their peptide-MHC ligands, which display a cross-section of peptides expressed by a particular cell. Despite their important role in protecting tumors, the identity and specificity of tumor-resident Tregs is poorly studied.  We are working to profile what T cells are enriched in low mutation rate cancers. We can then use approaches we have developed to find what these T cells as seeing in the tumor. This information will help us understand of one of the most important tumor-protective cell types, and may open the door to new cancer immunotherapies. 

Kexin Xu, Ph.D. & Virginia Kaklamani, M.D.

About 12% of U.S. women will develop invasive breast cancer over the course of her lifetime. Despite advances in early diagnosis and treatment of the disease, breast cancer remains the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer death in American women. Acquisition of resistance to current therapies is a major challenge in everyday clinical practice, which significantly reduces the disease-free survival and overall survival in breast cancer patients. Thus, it is important to develop new therapeutic approaches for circumvention of resistance and also to identify predictive biomarkers for more effective treatment decisions. Our previous work found a protein called EZH2 as a very promising therapeutic target in metastatic breast cancer that becomes refractory to hormone therapy. Several highly selective inhibitors of EZH2 are currently being tested in phase I/II clinical trials in patients with B-cell lymphoma. In this study, we will evaluate the efficacy of these EZH2-targeting drugs in metastatic, endocrine resistant breast cancer. We further demonstrated that DNA methylation of one of EZH2-regulated target genes, called GREB1, is highly associated with EZH2 activity in advanced breast cancer. So we will test whether methylation of GREB1 can be used to identify patients who will respond to EZH2 inhibitors. Results from this clinical study provide a novel targeted therapy for advanced breast cancer and a biomarker for choosing the right treatment. Our work will pave the way for the development of personalized medicine as an alternative approach to fighting metastatic, endocrine therapy resistant breast cancer.

Judith Varner, Ph.D.

Great strides have been made toward finding cures for cancer, which is expected to strike 1.6 million Americans this year. Although many cancer patients still die from their disease, the overall cancer death rate is declining due to improved detection methods and novel therapies. The exciting development of immune therapy has shown that activating a patient’s own immune system to attack and kill cancer cells can lead to cancer cures and improved life spans for patients with many forms of cancer. However, there are still many patients whose tumors are resistant to immune therapy. We recently found that tumor associated macrophages, immune cells that are found in great numbers in tumors, cause resistance to immune therapy. We identified new drugs that break this resistance to immune therapy; these drugs led to cures in animals with cancer. We will test these drugs in patients with head and neck squamous cell carcinoma, monitoring for changes in biomarkers of immune suppression and tumor progression. We will also identify new immune therapy drug combinations that can improve cancer care. These studies will contribute to the development of novel, effective immune therapies for cancer patients.

Michael Taylor, M.D., Ph.D., FRCS

Funded in partnership with WWE in honor of Connor’s Cure

Medulloblastoma is the most common malignant brain tumor in children. Medulloblastoma is really made up of four diseases, of which two types: Group 3 and Group 4 account for the majority of cases. The main tumor ‘lump’ in the brain is called the ‘primary tumor’. The primary tumor can spread (metastasize) to cover other regions of the surface of the brain and spinal cord. Most children who die from medulloblastoma die because the tumor has spread (metastasized) and not due to the primary tumor. The most damaging therapies (radiation) for children with Group 3 and Group 4 medulloblastoma are necessary to treat the metastases.

For the most part, medulloblastoma only spreads to the surface of the brain and spinal cord, and not to other organs. According to the textbooks this occurs when cells drop off the primary tumor, float around in the spinal fluid, and then reattach to the brain or spinal cord and start growing again. There really is no evidence or experiments to support this mechanism, just historical speculation. We have now shown that in fact, medulloblastoma spreads through the blood stream—the cells enter the blood stream, and then home back to the brain and spinal cord where they grow and kill the child.

This new understanding of the metastatic process for medulloblastoma offers fresh opportunities to non-invasively diagnose medulloblastoma in the blood, to prevent the metastatic cascade, prevent the progression of metastases, and decrease the toxicity of therapy for children with medulloblastoma.

Ben Stanger, Ph.D., M.D.

Cancer is caused by genetic changes (errors), making every cancer unique. Nevertheless, cancers share features that allow them to be grouped into categories or “subtypes.” A tumor’s subtype strongly influences its behavior, including growth rate, likelihood of responding to one therapy versus another, and probability of relapse. Knowing each tumor’s subtype could thus help determine which therapy is best for a give a patient, a concept known as “Precision Medicine.” Currently, subtype can only be determined by in-depth sequencing of tumor tissue, and thus it is not routinely determined in clinical practice.

The goal of this proposal is to develop a rapid, non-invasive, and inexpensive way to determine tumor subtype from a blood test. This is called “liquid biopsy,” and it is playing an increasingly important role in cancer care. Because liquid biopsies are non-invasive (i.e. they do not require surgery or other procedures), samples can be obtained repeatedly over a course of therapy, allowing better clinical decisions to be made.

Colorectal cancer (CRC) is the second-leading cause of cancer death in the United States, where it has a disproportionately lethal effect on African-Americans. Recently, a consensus panel concluded that the disease has four major subtypes based on patterns of gene expression (which genes are “on” or “off” in the tumors). In this proposal, we will use these
definitions to perform subtyping from liquid biopsies. In the future, the approaches we will develop here will be applicable to all cancers, not just those affecting the colon and rectum.

Joseph Sparano, M.D.

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women. The primary cause of death is metastasis, or spread of the cancer via the blood stream to other organs, which is incurable and associated with an average life expectancy of only 3 years. Although breast cancer death rates have declined due to screening and more effective treatments, more accurately identifying metastatic risk in order to prevent overtreatment remains a major clinical challenge. Therefore, the most important problems in breast cancer include reducing overtreatment by identifying more accurate prognostic markers and preventing spread of cancer cells in those at risk. Our program has focused on addressing these problems by studying breast cancer cell dissemination at single cell resolution using innovative experimental methods, with a focus on translating these discoveries into the clinic through multidisciplinary collaboration. In aim 1, we will confirm the association of 2 specific breast cancer tests that may more accurately identify who is at risk for recurrence, one of which identifies microscopic structures (which we call “TMEM”) that seed tumor cells into the blood and other organs. In aim 2, we will test a new drug which blocks TMEM function to see if it can block seeding of tumor cells into the blood. The project is therefore studies an entirely new approach to cancer diagnostics and treatment. The basic science studies that led to this work have been described in an award winning video entitled “Spying on Breast Cancer Metastasis” (https://www.youtube.com/watch?v=q_JDp-VePAs)

Barbara Savoldo, Ph.D., M.D.

The administration of a subset of human immune cells cultured in the laboratory and known as T lymphocytes that have been engineered to express a chimeric molecule that recognizes tumor cells has shown remarkable antitumor effects in patients with blood tumors. Although there is much promise in these therapies, there is still a need for improvement in safety and efficacy. This project is important to patients because it examines a considerable challenge with these therapies, e.g. their toxicities. The way toxicities are being addressed in this project is unique and holds the promise of alleviating many severe side effects experienced by patients. Additionally, controlling toxicities will be extremely important to the success of treating patients with solid tumors when normal tissues may be targeted.  So, there are many advantages to the “safety switch” approach that we propose in this application to alleviate side effects.