Game-Changer Archives - Page 7 of 45

J. Silvio Gutkind, PhD

Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need

Cancer immunotherapies have led to major treatment breakthroughs for a number of different cancers, but the majority of head and neck cancer patients do not respond to immunotherapies, and clinical responses are often not durable. Excitingly, we have demonstrated that targeting aberrant signaling networks in head and neck cancers can also influence anti-cancer immunity, supporting the development of novel, precision immune oncology therapies that significantly improve response profiles. The research outlined in this proposal will combine treatment with a targeted precision therapy – a highly selective anti-HER3 antibody – possessing both direct tumor and immune microenvironment activity, with PD-1 inhibitor immunotherapy. Leveraging our tobacco-signature oral cavity squamous cell carcinoma mouse model, we have obtained strong preliminary results supporting that our therapeutic combination – anti-HER3 + anti-PD-1 – 1) abolishes cancer-driving signaling pathways, 2) reverses the immunosuppressive microenvironment, and 3) potentiates existing antitumor immunity to achieve durable response. In order to develop more effective multimodal immune-oncology therapies that achieve durable response, we propose to employ several innovative techniques with single-cell level resolution to study the tumor-intrinsic effects of targeted HER3 blockade and how these changes ultimately invigorate and synergize with immunotherapies. Our novel approach represents a paradigm-shift in the design of cancer therapies – one in which therapies are rationally selected to target not only specific oncogenic pathways but also to activate cancer immunosurveillance. The proposed studies will provide the first signal-transduction based multimodal precision immunotherapy for head and neck cancer.

Tullia Carmela Bruno, PhD

Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need

Our immune systems are internal barometers for the primary response to foreign invaders like viruses and bacteria within our body. Despite cancer arising from irregular growth of our own cells, the immune system can effectively kill cancer cells just as it identifies and kills infected cells. However, cancer can also effectively hide from the immune response (known as immune evasion), specifically because it grows from our normal cells becoming mutated or unchecked. Thus, preventing immune evasion and augmenting the immune response are now the focus of new and promising treatments. The immune cells found in cancer can be classified by function, helpers, killers, and suppressors. Helpers educate the killers. Killers directly attack and eliminate the tumor cells. Suppressors hinder the immune response and promote cancer growth. Most immune-based therapies target the killers, however, there are many other components of the microenvironment in which cancer grows. In addition to the helpers and suppressors, the “soil” in which these cells thrive is important. We aim to understand how the “soil” (known as mesenchymal stem cells, MSCs) influences two key immune components in ovarian cancer patients, helper educational centers known as tertiary lymphoid structures (TLS) and suppressive T cells known as T regulatory cells (Tregs). Understanding this interplay is paramount to generating new and effective therapies for ovarian cancer patients, which is especially important in ovarian cancer because patients have not garnered the same therapeutic benefit with immune-based therapies as other solid tumors. In fact, only ~10% of ovarian cancer patients receive a survival benefit with immune-based therapies. Why is this? What is unique about ovarian cancer than allows it to effectively hide from the immune system?

In ovarian cancer, the balance of the immune response is often tipped to enhance the suppressors, thus killers cannot effectively target and kill the tumor cells. We aim to determine how to increase the “soil” (MSCs) that promotes helper TLS and prevents suppressive Tregs utilizing novel therapies. “Soil” cells which start in the bone marrow (BM-MSCs) can initiate the building of helper TLS. Thus, these BM-MSCs work with the immune system to increase anti-cancer immunity. “Soil” cells that develop within the ovarian cancer environment (CA-MSCs) can help enhance ovarian cancer growth by amplifying the suppressive function of Tregs. Thus, these local CA-MSCs work against the immune system to decrease anti-cancer immunity.

Altering the immune balance by targeting both the immune cells and the MSCs offers powerful new combinatorial treatment approaches. Our goal is to understand the specific factors within the ovarian cancer environment which impact this immune balance and to develop treatments to shift this balance to kill ovarian cancer. Specifically, we will study the steps necessary for BM-MSCs to support TLS formation and immune activation. We will also identify how local CA-MSCs recruit Tregs to decrease the immune response. We will specifically test if blocking the interaction between CA-MSCs and Tregs will shift the balance of immunity towards killing cancer.

This work can be quickly moved into clinical trials as the blocking drug we are testing (neuropilin-1; NRP1) is already in early clinical development and our team includes an ovarian cancer clinician and translational immunologist with experience writing, conducting and analyzing clinical trials. The vision of the Clinic and Laboratory Integration Program (CLIP) is to improve the effectiveness of cancer immunotherapies. This grant will meet this vision by developing a therapy that targets MSCs and the immune system for a synergistic effect on improved patient outcomes.

Luisa Cimmino, PhD

Funded in partnership with Miami Dolphins Foundation

Vitamins play an essential role in keeping our immune system healthy by maintaining normal blood cell production. Certain types of vitamins can also help in the prevention and treatment of blood cancers. Vitamin A has been used for decades to treat a subset of blood cancer patients with defects in a protein that relies on vitamin A for its normal activity. More recently, our work has shown that vitamin C can also stop blood cancers from forming, and slow cancer growth, by maintaining or restoring the activity of a protein known as TET2. Loss of TET2 function causes an increase in the growth of blood cells that drive cancer development. Mutations in TET2 that lower its activity are frequently found in patients with blood cancers. TET2 is also frequently defective in the blood cells of the healthy elderly population that can put them at a much greater risk of developing a blood cancer. The goal of our work is to understand how we can maintain TET2 activity to prevent and block cancers of the blood. Interestingly, vitamin A treatment can increase TET2 levels in cells, which in combination with vitamin C restores TET2 activity more than either treatment alone to stop the growth of blood cancer. Our goal in this study is to model combination treatment strategies of vitamin A and vitamin C to prevent blood cancer formation and growth that can be used as a potential therapy to treat blood cancer patients with a loss in TET2 activity.

Lourdes Baezconde-Garbanati, PhD

Funded in collaboration with ESPN

Even if cancer therapeutics and cures were found, they may not benefit African Americans and other under-represented minorities, due in part to a lack of participation in clinical cancer trials and cancer disparities research. Los Angeles has the seventh largest population of Blacks in the United States. Although many may think this population is homogeneous, there are still differences among individuals who identify as Blacks in Los Angeles. This population includes not only individuals born in the U.S. of African ancestry, but also foreign-born including of African or Afro-Caribbean origin. If we are to truly achieve “Victory over Cancer”, under-represented minorities, including all segments of the African American community need to engage in the research process. This grant will allow for holding focus groups with various segments of the AA community, achieving a greater understanding of barriers to CT and acceptance of precision medicine research. We will be able to obtain information for the creation of an outreach and awareness raising tool kit to work with AA community leaders, faith based and other organizations, in advancing knowledge and changing attitudes towards CT participation, provision of biospecimens and inclusion of AA communities in cancer disparities research.

Nita Lee, MD, MPH

Funded in collaboration with ESPN

EMPOWERED U is a community research program to better understand and address the gaps in cancer research in our diverse communities. Black or African American (AA) patients have lower rates of joining cancer prevention or treatment clinical trials. For many cancers, Black or AA patients are still diagnosed later or may not live as long as white patients. Many factors such as insurance, poverty, age, other diseases, racism and bias in treatment, and trust of medical research due to prior racism may cause these differences. As science for cancer treatment advances, the gap will increase if not everyone has equal access to new technology. Patients may miss the chance to join new trials and researchers may miss the chance to better understand disease and treatments in diverse groups.

This program partners directly with community members to study opinions from patients, caregivers, local community leaders, and medical providers to better understand barriers, myths, fears as well as factors that can improve trials participation and the patient experience.

The patient and community voice will be captured in focus groups and interviews. The community research team will use this important input to design a Community Clinical Trials Toolkit (booklets, print cards and videos) to better answer questions and worries and support patients to learn about clinical trials. Importantly, we will also create community led education for providers and clinical research teams about community and patient perspectives and best practices to support patients.

Hanlee Ji, MD

Funded by Gastric Cancer Foundation

With an extensive cohort of gastric cancer genomic data, there are many new avenues for translational research and clinical investigations. Importantly, a registry this size provides significant degree of statistical power, thus providing researchers with an invaluable resource. Researchers and clinicians in any discipline and at any institution across the world may access this data for independent discovery and validation studies. For example, an investigator may access the data to answer the question, “I found that H. pylori infected patients often have downstream functional mutation in the gene MUC1; can this finding be replicated in another patient population?” The end results may be a new practical and scalable early detection technology, or a precision therapy for gastric cancer patients. Ultimately, the GCR is designed to be a resource for accelerating gastric cancer research.

Michael Verneris, MD & Steven Dow, DVM, PhD

Funded by the 2019 Wine Celebration Fund a Need for Canine Comparative Oncology

Osteosarcoma (OS) is a common and devastating cancer of the bone which occurs in both dogs and humans. Upon diagnosis, the majority of dogs require amputation and chemotherapy. Despite this, most relapse within a year of diagnosis. In humans, OS is the most common bone tumor of adolescents and young adults (AYA). Pediatric and AYA patients with metastatic OS at diagnosis or who relapse after frontline therapy have an extraordinarily poor prognosis, with only a 20-30% survival at 5-years. Despite concerted attempts, these outcomes have not changed in >25 years.

Due to similarities in genetics, biologic behavior and treatment responses, canine OS is considered the best model of pediatric and AYA OS. We have used this model to investigate new immunotherapies and some of these have been translated into human trials (NCT03900793). In preliminary studies, we have determined that canine OS overexpress a protein known as B7-H3, which is absent in normal dog tissues (heart, liver, brain, kidney and spleen). We also find that both dog and human OS are infiltrated with tumor associated macrophage (TAM), which suppress immune responses to the tumor. The Dow lab has designed and tested methods to deplete these TAMs and the Verneris lab has been testing ways to target B7H3 using cellular immunotherapy with chimeric antigen receptors (CARs). Here, we will bring these two approaches together to test whether the improve outcomes in rodent xenograft models and in pet dogs with macroscopic pulmonary OS metastases in a clinical trial at CSU.

Sascha Tuchman, MD, MHS

Funded by the 2020 Victory Ride to Cure Cancer

African Americans develop a form of blood cancer called multiple myeloma more often than Caucasians. On average, African Americans live less long with it. That may be in part because African Americans take part in clinical trials less often. Clinical trials are studies designed to develop new treatment drugs. Those trials can sometimes help people to live longer with this illness. We are trying to improve how many take part in clinical trials at UNC. We are creating an easier, more comfortable doctors’ office to get care at and take part in trials at UNC. We are making it easier for African American researchers at UNC to work on this important issue. We will make a video that shows what clinical research is. It will show why it can be helpful to take part in research. The video will be shown to African Americans and other patients treated at UNC. The UNC team will compare how many African Americans join multiple myeloma trials before and during this grant. If more African Americans enroll in multiple myeloma trials after the grant begins, it would show that these efforts have helped solve this problem. That may help African Americans with multiple myeloma to live longer. IT will also help make important progress in this research.

Linda Sutton, MD

Funded by the 2020 Victory Ride to Cure Cancer

Cancer is caused by changes that happen in the genes of cancer cells. Special tests can find genes that start or promote cancer growth. New drugs can target cancer causing genes and kill cancer cells. The Duke project team wants to increase awareness and use of both the special tests and the new drugs. The project will bring a group of experts together to talk about patient cases and help find the best medicine for patients. If medicines are not available, the project team can find clinical trial options for patients. The team will also provide training to doctors and nurses on new tests for cancer genes and medicines. We will create information to help patients learn about the special gene tests and how the results can help the doctors choose the right medicine to treat their cancer. When the project is finished, the team hopes to provide the information and tools created to other local doctor’s offices and patients.

Manali Bhave, MD

Funded by Hooters of America, LLC

There have been significant advances in the treatment of patients living with metastatic breast cancer. Some of these advances are due to a fairly new type of technology looking at changes in the DNA of the tumor (somatic next-generation sequencing (NGS)) and/or in patient’s normal cells (germline NGS) that may impact a patient’s prognosis and/or treatment options, including the opportunity to enroll on clinical trials.

Very few studies have looked at patient understanding and knowledge on this type of advanced testing (next-generation sequencing), though of the studies available, there appears to be a low level of patient knowledge on next-generation sequencing and a gap in expectations as to how this form of testing can impact a patient’s clinical care.

The aim of our study is to increase the enrollment of patients with metastatic breast cancer into clinical trials that match patients to specific therapies based on their NGS through 1) increasing patient knowledge and understanding of NGS and 2) using the education tool to identify the change in the rate of NGS testing, as well as change of treatment recommendations based on these results.