Translational Archives - Page 11 of 30

Irene Ghobrial, MD

Funded by the Stuart Scott Memorial Cancer Research Fund

We believe that the immune system in patients with a precursor condition to multiple myeloma (a cancer in the bone marrow) allows the disease to progress (worsen) into more serious disease. Our project aims to find immune biomarkers that predict disease progression and identify patients who will likely progress early to treat the most at-risk patients before they become symptomatic. These markers may include changes in the number or type of immune cells or changes in the way those cells work. We will also examine how patients’ immune systems change in response to a new treatment that targets immune cells. We will use DNA and RNA sequencing and spatial imaging to investigate single cells from the bone marrow. We will gain a detailed picture of how the immune system supports or fights the tumor. This work will support the development of new treatments that may slow or stop disease progression.

Robert Canter, MD

Immunotherapy has transformed cancer therapy and positively impacted the lives of many patients. However, despite these advances, there remain barriers to the success of immunotherapy, and a majority of patients do not get better from immunotherapy. Unfortunately, soft tissue sarcomas are among the cancers which do not respond well to current immunotherapies, and the survival rate for these rare and difficult-to-treat cancers has barely improved for many years. Therefore, more research is needed to extend the benefits of immunotherapy to sarcoma patients.

The past decade has witnessed a big increase in research on natural killer (NK) cells. NK cells are a part of the immune system and are able to rapidly attack bacteria and cancer cells. Despite their ability to kill tumor cells, success with NK cells in cancer patients has hit roadblocks, in part because these cells lose killing capacity quickly, likely so the body can control them. This proposal seeks to understand how this exhaustion of NK cells can be overcome to better fulfill the promise of NK immunotherapy. We will block a novel receptor (TIGIT) on NK cells since this receptor is consistently upregulated on NK cells. We will use a diverse approach, including mice and human sarcoma samples. Then, we will pilot our new immunotherapy approach using NK cells and TIGIT blockade to release the brakes in a first-in-dog clinical trial for dog patients with soft tissue sarcomas. Cancer is a leading cause of death in dogs, as it is for humans.

Zhaoming Wang, PhD

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

Survivors of childhood cancer are at high risk of late health problems related to cancer treatment. Our early work suggested that health problems differ among survivors based on social-economic status like level of education, household/personal income, and the neighborhood in which they live. In the proposed research, we will describe and measure differences in health problems among childhood cancer survivors based on the social-economic status. We will focus on common health problems including obesity, high blood fat levels (triglycerides or cholesterol), abnormal blood sugar control, high blood pressure, heart muscle weakness, and heart attack. We will use stored blood samples and data already available from the St. Jude Lifetime Cohort Study to study biologic changes that may predict a survivor’s risk of health problems and links to social-economic factors. We hope that the results of this work will help identify survivors at higher risk for health problems and guide new research aiming to reduce, reverse, or prevent the harmful effects of social-economic factors on health problems after treatment for childhood cancer.

Ulrike Peters, PhD

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

Colorectal cancer starts in the large intestine. It is the second leading cause of cancer death in men and women in the US. Alaska Native people have among the highest rates of colorectal cancer in the world. Alaska Native people also die more often of this disease than any other racial or ethnic group in the US. The reasons for these health disparities are not fully understood.

Almost no research exists on molecular changes in Alaska Native colorectal cancer tumors. In this study, we will look at the genes expressed in these tumors. Genes code for proteins which support normal cell function. Changes to genes may result in abnormal growth of the cells resulting in cancer. Studying gene expression tells us which genes in the tumor may be causing the cancer and will help us understand more about the patterns of gene expression among Alaska Native colorectal cancer patients. We will also examine if tumor gene expression can tell us which patients will live longer with their cancer.

This research will help to identify colorectal cancer patients with aggressive disease at diagnosis. This could help to guide clinical decision making and improve disease outcomes. Also, this research may tell us if Alaska Native colorectal cancer patients might benefit from available or new treatments.

Jennifer Doherty, PhD, MS

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

Ovarian cancer is a leading cause of cancer death among US women, with about 50% of women dying from their disease within five years. Treatments including surgery and chemotherapy are meant to cure the cancer, but in about 50% of women, the cancer will come back.

Black and Hispanic women are more likely to stop treatment early, and to die from their disease than non-Hispanic white women. These differences are referred to as race/ethnic disparities. There are many reasons for disparities, including differences in access and quality of medical care. Black and Hispanic women are also more likely to have other health conditions (i.e. comorbidities), like heart disease or diabetes, when they are diagnosed with ovarian cancer. These comorbidities may change a patient’s ability to tolerate treatment, and in turn, may reduce their survival. Comorbidities may also change the biology of the tumor. Looking at tumor markers may provide information on response to treatment and survival of the patients.

The goal of this project is to understand race/ethnic disparities in ovarian cancer treatment, recurrence, and mortality. In this project, we will examine how comorbidities and tumor markers differ in a diverse group of ovarian cancer patients. This study will take place using data from the Kaiser Permanente Healthcare system. This research project will provide information for doctors about how health conditions can affect a woman’s response to treatment, so that she can get better cancer care, and help to reduce disparities in ovarian cancer treatment and outcomes.

Shannon Stott, PhD

Nick Valvano Translational Research Grant *

Brain tumors are the number one cause of pediatric cancer deaths. And despite advances in treatment, children in remission have both the constant worry of their tumor returning, plus long term (often delibitating) treatment-induced side effects. . As new treatments are developed, there is an urgent need to better monitor treatment response.

Due to their location, the most common tool for monitoring pediatric brain tumors is recurrent imaging ( such as a series of MRI imaging scans over time). While imaging can provide some information about current disease status in brain tumor patients, it can’t provide details on how the tumor has changed in response to therapy. To address this gap in technological capacity, our team has developed a less invasive blood test that can remove rare tumor cells and particles released by the tumor in brain tumor patients. This test requires less than a teaspoon of blood, which makes it ideal for pediatric patients. For this study, we will use our test on 60 pediatric cancer patients with gliomas and medulloblastomas, in order to detect and monitor the these biomarkers in the blood, and watch for changes to their levels throughout treatment. At the end of this study, we then plan to test our techology in multi-center clinical trials. Our long-term goal is to use tumor biomarkers in blood to more rapidly identify when brain cancer patients need to be retreated, which we hope can in turn be used to accelerate and improve therapeutic interventions.

Jun Qi, PhD

Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure

Dr. Jun Qi is a synthetic organic chemist and chemical biologist who has developed small molecules and pioneered a novel chemical strategy in which small molecule therapeutics can be designed to destroy specific proteins within a cell, as opposed to suppressing enzymatic function. Dr. Mariella Filbin is a physician scientist specializing in pediatric neuro-oncology with clinical and scientific interests converging upon pediatric brain cancers, in particular, diffuse intrinsic protein glioma (DIPG) which is universally fatal. Dr. Filbin has used patient-derived models to identify a potential DIPG-specific target for Dr. Qi’s protein degrader technology. They will work together to overcome challenges in childhood brain cancer treatment, such as toxicity and blood-brain-barrier (BBB) penetration. This exciting study has two broad objectives:

To define the mechanism by which the cancer dependent protein is driving DIPG formation and growth;
To yield optimized drug compounds suitable for preclinical study and translation to clinical trials in DIPG.

By working together as team, Drs. Qi and Filbin will cultivate a symmetrical relationship in which chemistry will be used to clarify the biology; and biology will be used to guide the small molecule design and development. By combining their complementary skill sets in chemistry, chemical biology and cancer biology, their joint efforts will result in the preclinical validation of eliminating the target genes and ideally the development of a clinical trial using this novel strategy for DIPG to achieve the bench-to-bedside translation of their research.

Christine Pratilas, MD

Bob Bast Translational Research Grant *

RAS is a gene that plays a major role in cancer. The three members of the RAS family are HRAS, NRAS, and KRAS. One of these genes is mutated in about 15% of cancers. The mutant form is hyperactive.
In pediatric solid tumors, RAS is mutated in about 1-3% of cancers and more often in rhabdomyosarcoma.
Inhibiting RAS activity has been a difficult task in cancer drug development. One type of drug, the farnesyl transferase inhibitors (FTI), were developed twenty years ago. Clinical trials using these drugs were disappointing. We now have a better understanding of how to select patients that will best respond to FTI.
Only mutant HRAS is dependent on the farnesyl transferase enzyme. So, FTI should work best in patients with HRAS mutant cancers.
In a clinical trial of patients with HRAS mutant head and neck cancer, patients were treated with tipifarnib, an FTI. Trial outcomes showed that patients’ tumors got smaller (responded).
We are now studying FTI in pediatric solid tumors. We want to know what adaptive events occur in the cell and whether these changes only occur in mutant HRAS tumors. We also want to learn how tumors may escape the anti-cancer effects of FTI.
Studying these changes and paths of resistance can help us develop more complete and lasting responses. Our study aims to address these issues to find effective treatments for patients with HRAS mutant cancer.

Robbie Majzner, MD

Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure

DIPG is a universally fatal brain tumor that occurs in children. Thanks to extensive research, we now understand the biologic causes of DIPG, but no one has found an effective way to treat the disease. Patients receive radiation to slow the disease and relieve symptoms, but they almost all die within two years of diagnosis. We have found that a target known as GD2 is highly expressed on DIPG. GD2 can be targeted with an antibody that is FDA approved to treat another type of cancer. When the antibody finds its target, it recruits immune cells to “eat” the cancer cells. Here, we propose combining anti-GD2 with another antibody that stimulates the immune system to “eat” cancer cells (anti-CD47). Because antibodies cannot reach the brain when given in the blood, we will deliver these two antibodies by direct injection into the tumor. Our main goal is to test this approach in mouse models of DIPG to see if it is safe and effective. This will hopefully serve as the basis for a clinical trial for children with DIPG. We will also explore alternative and complementary ways to attack the tumors.

Ian Davis, MD, PhD

Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure

Years of cancer research have shown that combining therapies virtually always works better than when therapies are used alone. Recently, medications have been discovered that change the way genes are turned on and off. At the same time, treatments have been developed that use the body’s own cells to find and attack cancer cells. Each of these treatments have been shown to work alone on specific cancers. Each has known limits. However, the combination has not been studied. Our project explores whether combining these treatments will improve our treatments for childhood cancer. We are especially interested in if combining these therapies will increase the success of cellular therapies. Our proposal initially studies one specific medication that is already approved for use in children. We will also evaluate a large group of possible medications. We expect that our results will quickly result in a clinical trial for children. In addition, it may lead to a new treatment approaches for many cancers.