Identification of angiopoietin-2/Tie signaling molecules as a predictive biomarkers for ICI resistance in melanoma
Identification of angiopoietin-2/Tie signaling molecules as a predictive biomarkers for ICI resistance in melanoma
Minah Kim, PhD
| Award Type | Pilot Proposal |
|---|---|
| Institution | Columbia University |
Description:
Although immune checkpoint inhibitors (ICI) such as programmed death-1 (PD-1) blockade have made meaningful advances in the treatment of melanoma, drug resistance has limited their therapeutic efficacy as approximately 70% of patients still experience disease progression within 5 years. Therefore, understanding mechanisms of ICI therapy resistance and identification of biomarkers for predicting response to ICI treatment are unmet needs. Along with new blood vessel formation in the tumor by angiogenic factors, vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Emerging evidence suggests a fundamental link between tumor vascular abnormalities and ICI therapy resistance whereby vascular destabilization impairs the immune cell infiltration to the tumor and promotes and immune evasion. Consistently, recent clinical and preclinical evidence has highlighted the importance of targeting proangiogenic factors to improve immunotherapy efficacy in cancer. Angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2, is a potent vessel-destabilizing factor and its upregulation correlates with poor prognosis and disease progression in many types of tumors. Building on our previous work on Ang2/Tie signaling in the tumor microenvironment, in this project we propose to identify Ang2/Tie signaling molecules as predictive biomarkers for immune evasion and ICI therapy resistance in melanoma. Successful completion of this project could significantly enhance the clinical management in patients with melanoma receiving ICI therapy.
Racial, Sex, and Socioeconomic Inequities in Melanoma Surgical Interventions & Outcomes: A Multivariate Analysis
Racial, Sex, and Socioeconomic Inequities in Melanoma Surgical Interventions & Outcomes: A Multivariate Analysis
Rewan Abdelwahab
| Mentor | Addison Demer, MD |
|---|---|
| Award Type | Medical Student Award |
| Institution | Mayo Foundation for Medical Education and Research |
| Donor Support | Honoring Richard Arthur Draeger from his Family |
Description:
Background: Racial inequities in melanoma survival have been documented in the literature. The largest Black-white difference in overall cancer survival is for melanoma and has been worsening in recent years. Surgery remains the standard of care for localized, primary cutaneous invasive melanoma.
Objective: To determine if differences in the time to intervention, surgical approaches, and surgical outcomes may contribute to the current, stark disparities in melanoma survival outcomes between non-Hispanic white and Black individuals.
Methods: Analysis of melanoma data from the National Cancer database from 2008 to 2017. The national cancer database is part of an ongoing collaboration between the Commission on Cancer of the American College of Surgeons and the American Cancer Society and is the largest clinical registry world, capturing
most of the cancer diagnosis in the United States.
Results: Controlling for other confounding factors such as type of melanoma, thickness of tumor, type of medical institutions among others, we seek to determine if differences exist in time to intervention, post-operative complications, and use of surgical techniques between non-Hispanic white and Black individuals.
Limitations: Database study, limited data on racial minority patients in database. Observational studies and retrospective analyses cannot prove causation but rather reveal correlations that may ultimately highlight areas of future study.
Conclusions: By identifying differences in melanoma surgical treatment among patients of varying racial/ethnic backgrounds, we ultimately hope to promote improved patient outcomes and reduce melanoma mortality through research-based interventions.
Identifying Cell-Intrinsic Mechanisms of Melanoma Suppression by APOE Variants
Identifying Cell-Intrinsic Mechanisms of Melanoma Suppression by APOE Variants
Nneoma Adaku
| Mentor | Sohail Tavazoie, MD, PhD |
|---|---|
| Award Type | Medical Student Award |
| Institution | The Rockefeller University |
| Donor Support | Honoring Richard Arthur Draeger from his Family |
Description:
Melanoma is a relatively uncommon form of skin cancer, but it is responsible for most skin cancer deaths because of its ability to metastasize, or spread throughout the body. In recent years many promising new treatments for melanoma have been developed, but most melanomas that have metastasized are still incurable. Therefore, we are particularly interested in understanding how melanoma cells leave the skin and travel to distant organs. We previously discovered that a protein called apolipoprotein E (APOE) helps slow the spread of melanoma cells in the body. There are three common types of APOE that every person is born with, which are called APOE2, APOE3, and APOE4. We recently found that these APOE types are not equal in their ability to slow melanoma spread, partly because the APOE4 version is best at activating the immune system to fight melanoma. However, we also know that melanoma cells in a dish behave less aggressively when treated with APOE4 compared to APOE2, even when immune cells are not present. This means that the APOE types have a direct effect on the melanoma cells themselves. Therefore, we believe that the APOE types differ in their ability to block a pro-cancer program that is active within melanoma cells. The goal of this project is to identify that program and therefore provide a new target for melanoma therapy.
Molecular Cell State Analysis of Hybrid Cells across the Uveal Melanoma Metastatic Cascade
Molecular Cell State Analysis of Hybrid Cells across the Uveal Melanoma Metastatic Cascade
Ashley Anderson
| Mentor | Melissa Wong, PhD; Summer Gibbs, PhD |
|---|---|
| Award Type | Medical Student Award |
| Institution | Oregon Health & Science University |
| Donor Support | Looney Legacy Foundation |
Description:
Hybrid cells, in circulation and in the tumor are reprogrammed cancer cells displaying immune cell mimicry—insights into their impact on tumor progression, immune cell interaction, and regulation of the tumor microenvironment have not yet been explored. In this study, I aim to characterize both the genotypes and phenotypes of hybrid cells in UM, drawing comparisons between hybrid cells across the metastatic cascade that will ultimately aid in our understanding of UM disease progression. Furthermore, I will evaluate RUNX1 pathway phenotypes across the metastatic cascade, as a means for facilitating hybrid cell dissemination. The study of hybrid cells in UM has great potential to uncover new biologic insights to neoplastic cell dissemination and ultimately lead to a greater understanding of targetable mechanisms of this process.
Nanoparticle Delivered Chemotherapy and Immunotherapy for Treatment of Cutaneous and Metastatic Melanoma
Nanoparticle Delivered Chemotherapy and Immunotherapy for Treatment of Cutaneous and Metastatic Melanoma
Jungsoo Chang
| Mentor | W. Mark Saltzman, PhD; Michael Girardi, MD, FAAD |
|---|---|
| Award Type | Medical Student Award |
| Institution | Yale University |
| Donor Support | Honoring Richard Arthur Draeger from his Family |
Description:
While several medications, immune stimulating agents, and radiation therapies have been developed and used for the treatment of melanoma, the treatment options often have systemic toxicity effects and can be limited in their treatment of metastasis. For melanoma, there are often cutaneous lesions that allow for direct destruction, and the destroyed cancer cells present a marker that can help stimulate our own immune cells to detect and kill other melanoma cells in the surrounding. Thus there is an unmet opportunity to use both the type of treatment options: local therapy and a systemic therapy, to help cause local destruction and boost the immune response against these cancer cells. Previously our groups have developed a drug delivery platform using bioadhesive, biodegradable nanoparticle molecules; these have increased local activity while decreased systemic effects—therefore it increases the
safety and efficacy of the drugs. The purpose of the research is to use these nanoparticles loaded with chemotherapy to target melanoma nodules and metastatic melanoma in conjunction with local or systemic immune stimulating agents. We will also be using nonadhesive nanoparticles that have increased drug retention and engineerable size to target lymph nodes to help boost the anti-cancer effects by encapsulating an immunostimulant. The approach is unique as we are proposing a method to kill the cancer cells using the nanoparticles and another immunomodulatory molecule to help train the immune system to recognize the metastatic melanoma cells. Targeting the lymph nodes will help boost the body’s own anti-cancer response while theoretically decreasing the off-target and systemic effects. We will be using the nanoparticles with chemotherapy for local injections against nodular melanoma and also assess
the combination therapy with local and systemic immunostimulation including CpG, anti-PD1, and our own immunostimulant loaded nanoparticles. We hypothesize that the nanoparticle delivery of these agents in conjunction with these molecules will lead to efficient regression/ elimination of melanoma and metastatic lesions.
Recent Comments