Grant Archive - Page 21 of 141

Marina Konopleva, MD, PhD

Nick Valvano Translational Research Grant*

Acute Myeloid Leukemia (AML) is a blood cancer that arises from cells that normally fight infections in the body. However, these cells can become fast-growing and hard to kill, which causes their over-production. Eventually, healthy cells in the blood stop working because the diseased cells take over. Patients with AML are often treated with a novel drug called Venetoclax, which kills the majority of AML cells. However, residual cancer cells that did not die eventually re-populate the body leading to the patient’s death. In this research proposal, we identified the protein BAX as a key effector of cancer cell killing by Venetoclax. We also made several scientific observations about Venetoclax and BAX that are critical to understanding why this drug works for some cancer cells and not others. A scientific goal of this V Foundation Award is to provide the scientific reasoning for why Venetoclax does not always work in AML patients. At the same time, a therapeutic goal is to examine the new drugs that directly activate BAX, which restores its ability to kill AML cells. Our scientific goal is to work together and to provide a deeper knowledge of cancer therapies with the aim of cancer cures.

Sana Karam, MD, PhD

Bob Bast Translational Research Grant*

Pancreatic cancer is deadly. The only treatment that can cure it is surgery to fully remove the tumor, but that is only an option when the cancer is caught early, which is rare. Radiation to shrink the tumor before surgery has been tried, but with little benefit. By studying both patient and mouse models, we discovered that while radiation can kill cancer cells and stimulate some good immune cells, it also can make the environment harsh, help cancer cells escape, and bring in some bad immune cells. It can also scar the tumor, making surgery harder. In lab studies, we found a molecule called STAT3 that enables radiation’s negative effects. When we blocked STAT3 in mice, we harvested the radiation’s good effects while blocking its bad ones. In this proposal, we are testing a pill for patients to take with radiation that blocks STAT3. This is the first time it is combined with radiation to treat pancreatic cancer in humans. In liver cancer, this drug was so effective that the FDA has prioritized it for trials. In our proposed trial, we will collect blood and tissue from pancreatic cancer patients before and after the pill and radiation and study how this combination affects the tumor and the patients’ immune system. We hope to develop a test that predicts patient response to the STAT3 blocker with radiation combo and to identify other ways the cancer cells escape.

Christina Curtis, PhD

Funded with support from Patti and Tom Larkins

While there are an increasing number of treatments for breast cancer, a sizeable number of patients develop resistance to these agents and experience disease recurrence. These numerous therapies have been enabled by our deepening understanding of the biology of breast cancer at the molecular and cellular levels, which continues to advance as a result of powerful technologies. To date most treatments have focused on targeting the molecular drivers present within tumor cells, it is increasingly apparent that the effective treatment of aggressive tumors, will necessitate strategies that harness the patient’s immune system to detect and eradicate tumor cells. Such immunotherapies have been highly effective in other tumor types, but their use has lagged breast cancer as this tumor type is thought to be immune cold. Here we perform detailed studies of breast tumor samples from patients enrolled clinical trials evaluating the efficacy of novel targeted and immunotherapeutic strategies in both early-stage and advanced breast cancers with the goal of uncovering the molecular hallmarks of tumors that respond to these agents, as well as those that do not. These studies harness powerful new technologies to study tumor tissue in its native context, while preserving spatial relationship between tumor cells and surrounding immune and stromal cells. This approach will uncover molecular interactions that can be exploited to overcome resistance and to optimize therapies across different subgroups of disease.

Katherine Tossas, PhD, MS

Cervical cancer can be prevented with regular exams that detect precancerous lesions. However, these lesions are common and their progression to cancer is uncertain, resulting in unnecessary invasive procedures such as biopsies and their associated consequences of pain, bleeding, and scarring. Black women are disproportionately affected by these lesions and respective consequences. Black women also have different vaginal microbiomes (VMB) than their white counterparts. The VMB, comprising microorganisms in the vagina, has been linked to these lesions and could be a target for improved screening.

Our preliminary data suggests that the VMB’s protective effect may be influenced by race. To understand whether racially distinct pathways contribute to precancerous lesions and what factors influence them, we will recruit 90 Black and 90 white women with abnormal cervical cancer screenings. We will analyze VMB profiles, HPV viral load, and stress levels at two timepoints. Our goals are to determine if racial differences exist in HPV and VMB dynamics and assess the role of stress in disparities of lesion regression. We will also explore how HPV and VMB changes mediate the stress-regression relationship differently based on race.

This research will improve our understanding of the impact of VMB, HPV, and stress on lesion regression and racial disparities. By uncovering these factors, we can develop targeted interventions to improve the health outcomes of all women.

Sarah Johnstone, MD, PhD

Cancer arises from alterations, termed mutations, of a cell’s genetic material (DNA). Understanding how different types of mutations promote cancer cell growth requires precise modeling of these mutations in tumor cells in order to discern how they specifically impact cell function. We propose to do this for two proteins that are frequently mutated in ovarian cancer. These proteins, CTCF and BORIS, bind to the DNA and can change the DNA’s structure to turn genes on or off. However, how their mutations affect the DNA binding for these two proteins and impact ovarian cancer cells is unclear. We propose to generate cellular models of BORIS and CTCF mutations and measure their impact on DNA structure and gene expression. From these data, we will discern the molecular alterations and functional consequences of their mutation. The goal is to define the mechanism by which these frequent mutations impact ovarian cancer cells, with the ultimate hope that such mechanistic insights can lead to novel therapeutic approaches to ovarian cancer.

Juliana Hofstatter Azambuja, PhD

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

Diffuse midline glioma (DMG) is a devastating and aggressive type of brain tumor that primarily affects children and young adults. Despite advancements in medical research, DMG remains a medical challenge with limited treatment options and a poor outcomes. Considering these difficulties, there is an urgent unmet need to develop new and innovative therapies for DMG. One promising avenue for discovery is the exploration of targeted agents that disrupt key signaling pathways involved in tumor progression without affecting the healthy normal cells in the brain. Our previous work has identified a potential new therapeutic target that could be leveraged in this way to specifically combat this tumor. New drugs that selectively inhibit this aberrant signaling pathway show great potential for slowing down the growth of DMG cells, thus creating a new opportunity for intervention. In these proposed studies, we will explore precisely how this intracellular signaling pathway controls cancer progression. Further, we will test in the lab whether treatment with new drugs designed to inhibit this pathway can halt DMG tumor growth. We hope that our studies inform the use of new targeted drugs to treat this devastating childhood cancer and thereby drive advancement of patient care and redefine the treatment of DMG.

Eva Hernando-Monge, PhD

Most people who die from skin cancer died because their cancer has spread to the brain. Recent progress in treating patients whose cancer has spread to other organs has not kept pace for patients in whom skin cancer spread to the brain. At least part of the reason for this is likely because the environment in the brain is so different from other parts of the body. To address this urgent need for better treatments developed specifically for patients with skin cancer who then develop brain tumors, we looked for genes that might help cancer cells that spread from the skin to adapt so they can do well in the brain. We have identified a molecule that explain how it might help skin cancer cells to adapt to the brain. Already, we have encouraging evidence of how this molecule allows tumor cells to survive and grow inside the brain. Equally exciting is that there are already ways to block this gene function by taking a pill or injection, which will allow us to test if we can prevent or reverse the spread of skin cancer to the brain in our models, and eventually in patients. However, we first need to better understand exactly how important this process is in helping skin cancer cells to adapt to the brain microenvironment, and gather more information about how this gene seems to help skin cancer cells to invade the brain and adapt to a new environment.

Kelly Bolton, MD, PhD

Myeloid neoplasms (MN), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are fatal diseases because they are highly resistant to therapy. Ultimately, efforts at preventing MN might be the most successful way to eradicate this disease. Clonal hematopoiesis (CH) is thought to be the origin of MN. CH is a process whereby a hematopoietic stem or progenitor cell (HSPC) acquires a mutation (alteration in the nucleic acid sequence) that leads to a growth advantage compared to normal HSPCs. CH can be detected many years prior to a person developing MN but as of yet, there are no established therapies to prevent progression of CH to MN. We hypothesize that CDK4/6 inhibition might be a potential treatment to prevent MN through halting the progression of CH. Here we seek to: 1) further characterize the potential of CDK4/6 inhibitors to prevent CH expansion through analysis of pre-existing clinical trial data; and 2) using mouse modeling evaluate the potential of CDK4/6 inhibitors to inhibit CH independent of chemotherapy. If successful, this work will justify the development of clinical trials using CDK4/6 inhibitors to prevent CH from progressing to MN in high-risk populations. In the long term, we hope to use targeted approaches to eradicate high risk CH mutations to prevent the development of MN.

Sarah Adams, MD

Immune therapy has introduced a new way to treat cancer. One type of immune therapy is called PD1 immune checkpoint inhibition (ICI). PD1 ICI has enabled some people with melanoma and other cancers to live longer. These people have specific features on their tumors that are called biomarkers. People without these biomarkers do not respond as well to PD1 ICI therapy.

Our lab recently showed that a combination of two drugs can completely clear tumors in mice. One drug is a type of immune therapy called CTLA4 ICI; the other is an oral cancer drug called a PARP inhibitor. We developed two clinical trials to test this combination in people.
In the first clinical trial, we showed that people who lived longer had a new biomarker called VSTM5. In the second clinical trial, we will confirm that this biomarker predicts who will live longer when given this drug combination.

In this project, we will study why the VSTM5 biomarker predicts a response to the CTLA4 ICI therapy. We will use these results to select people who are likely to respond to CTLA4 ICI therapy. Our goal is to help more people get immune therapies that help them. We also want to help develop new types of treatments for ovarian and other cancers.

Ly Vu, PhD

Acute myeloid leukemia (AML) is one of the most common and aggressive types of blood cancers. Even though we have made exciting progress and have stronger treatments available, around 30% of AML patients who receive treatment will experience a relapse and have a very low chance of survival. Therefore, we need to figure out how these diseases develop and become resistant to treatment. It has been proposed in AML, there are certain cells that have stem cell-like qualities, which allow them to evade therapy and cause the cancer to come back even after treatment. In this project, we will use advanced techniques to investigate how these cells acquire such characteristics by having specific chemical changes on messenger RNAs. Our ultimate goal is to develop new treatments that can improve the lives of people suffering from these deadly diseases.