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Funded Research

Analysis and Expansion of the Pediatric Melanoma Outcomes Database Study

Analysis and Expansion of the Pediatric Melanoma Outcomes Database Study

Analysis and Expansion of the Pediatric Melanoma Outcomes Database Study

Brittani Seynnaeve, MD

Mentor John Kirkwood, MD
Award Type Career Development Award
Institution University of Pittsburgh
Donor Support Generously funded by the Inaugural #GetNakedJax Beach Bash

Description:

Melanoma is a type of skin cancer that develops when melanocytes (the cells that give the skin its tan or brown color) grow out of control. It is more dangerous than most other skin cancers because it is much more likely to spread to other parts of the body. In 2021, there will be an estimated 101,280 new cases and 7,180 deaths due to melanoma of the skin. In children, melanoma is the most common skin cancer, yet only makes up less than 1% of the total new melanoma cases. In the teenager and young adult age group, melanoma is the third most common cancer diagnosis.

We know that there are often differences in the way that pediatric melanoma looks on the skin. We also know that parents and doctors often do not know that children can get melanoma. Children often have better outcomes than adults with melanoma, though we don’t know how to predict which children may have their melanoma spread to other parts of their body and cause death. Because of these differences, pediatric melanoma is often caught late and even once diagnosed, doctors often aren’t sure how to treat it. This is a problem because we know that catching melanoma early is very important and can lead to the cancer being an earlier stage and patients requiring less treatment and having better outcomes.

Since pediatric melanoma makes up such a small number of overall melanomas, it has been difficult to study. The goal of this research project is to now study the information from hundreds of pediatric melanoma patients over many years from different hospitals from our retrospective database that we created so that we can better understand pediatric melanoma and be able to create pediatric melanoma treatment guidelines. Our improved understanding and standardization of care will lead to better outcomes for the patients diagnosed with this cancer.

The second part of this study will focus on growing our research groundwork through the creation of a “prospective database” to be able to continually study pediatric melanoma as changes and improvements are made in the care of adult melanoma. We will be able to collect patient information when first diagnosed and over time as they are treated and monitored by their medical team. Pediatric melanoma patients from all over the nation will be able to participate in this important research. We will also include very important information from the patient and parent perspective by asking participants to complete surveys about their experience with melanoma. We believe it is very important not only to increase our ability to treat pediatric melanoma, but to also understand the patient/parent experience during the process. The study will be further enhanced by including access to melanoma tumor samples, as well as photography documentation of the skin lesions before and after treatment, to fully pave the way for ongoing research and improvement of our care of pediatric melanoma.

Therapeutic Resistance to CDK4/6 inhibitors in BRAF-mutant Melanoma

Therapeutic Resistance to CDK4/6 inhibitors in BRAF-mutant Melanoma

Therapeutic Resistance to CDK4/6 inhibitors in BRAF-mutant Melanoma

Hee Won Yang, PhD

Co-PI Gary Schwartz, MD & Minah Kim, PhD
Mentor Richard Baer, PhD
Award Type Career Development Award
Institution Columbia University College of Physicians and Surgeons

Description:

In the U.S. alone during 2021, an estimated 106,110 and 101,280 people will be diagnosed with invasive and non-invasive (in situ) melanoma, respectively. Moreover, it is expected that 7,180 people will die from melanoma in 2021 and metastatic melanoma will be responsible for the vast majority of those deaths. In addition, invasive melanoma incidence rates have recently increased by ~2% per year.

To design therapeutic strategies and cure melanoma, we will need to identify the mechanisms that drive the disease. Mutations in genes associated with cell proliferation cause cancer. In melanoma, BRAF is the most frequently mutated gene, causing over 50% of all melanoma cases. Active BRAF mutations over-activate cyclin dependent kinase 4 and 6 (CDK4/6) to initiate cell proliferation, thus leading to the abnormal cell growth. Indeed, CDK4/6 inhibitor-based therapies have shown promising preclinical and clinical outcomes and are superior to the standard BRAF/MEK inhibitor therapy for treating metastatic melanoma harboring BRAF mutations. However, drug resistance severely limits the success of CDK4/6 inhibitor-based therapies. Here we propose to study the underlying molecular mechanisms of resistance to CDK4/6 inhibitors. Furthermore, our interdisciplinary team will evaluate the therapeutic effect of our new strategy for overcoming resistance.

Elucidating the molecular mechanisms behind drug resistance is challenging given the rarity of resistant cells, tumor heterogeneity, and plasticity of individual cancer cells. Current methods based on bulk analysis of tumor cell populations are insufficient to address how small subsets of melanoma cells can develop resistance to CDK4/6 inhibitors. By tracking thousands of cells at the single-cell level over multiple days, our strategy allows us to 1) isolate individual cells developing drug resistance and 2) monitor key steps to determine when and how subsets of cells develop drug resistance. Using these cutting-edge approaches, we will elucidate how drug-resistant cells differ from non-resistant cells and how these phenotypes contribute to CDK4/6 inhibitor resistance in BRAF-mutant melanoma.

Outcomes from this proposal will provide new insights into the molecular mechanism underlying resistance and new therapeutic strategies to overcome resistance to CDK4/6 inhibitors in melanoma. This collaboration between basic and translational investigators has the potential to advance novel drug combinations into human clinical trials that will first focus on BRAF-mutant melanoma. If successful, we anticipate that our approach might be relevant for other types of melanoma and potentially other types of cancer.

Targeted intervention of melanoma by reprogramming the stromal translatome

Targeted intervention of melanoma by reprogramming the stromal translatome

Targeted intervention of melanoma by reprogramming the stromal translatome

Yangpeiwei Huang, PhD

Mentor Davide Ruggero, PhD
Award Type Career Development Award
Institution University of California, San Francisco
Donor Support Generously funded by the Silverstein Family Research Challenge Grant

Description:

Gender is an important factor in patients with melanoma. Female melanoma patients have an advantage over their male counterparts in terms of survival. However, the reason for the gender disparity in melanoma prognosis is poorly understood. Sex is an important variable in tumor pathogenesis and therapy responses; but there are few reports describing potential sex-based differences in potential sex-based differential responses to tumor therapy. The lack of sex-based differences in study design led to the failure to analyze differences in drug efficacy and side-effect profiles. Therefore, deciphering the gender differences in melanoma will benefit the design of sex-based therapeutic regimens.

Melanomas are composed of a repertoire of non-tumor cells, such as immune cells, fibroblasts and endothelial cells, which co-evolve with tumor cells and contribute to tumor development. The stromal cells sensitively respond to changes in the tumor microenvironment (TME) during malignant transformation and therefore require rapid adaptations in gene expression, which relies on the efficient protein synthesis. Interestingly, I found that the key translation initiation factor, eIF4E, might be the missing link between translational remodeling of the TME and environmental factors driving melanoma sex disparities.

The goal of this proposal is to characterize eIF4E-mediated sex-related differences in melanoma progression and test the therapeutic potential of targeting eIF4E in both genders. In my preliminary studies, I have obtained evidence that immune microenvironment is drastically influenced by eIF4E dose in female mice but not in males, suggesting that eIF4E is essential for suppressing anti-tumor immunity in females. In this proposal, I will define eIF4E dose-mediated gender-dependent alterations of immune microenvironment and how they influence melanoma progression. I will further identify eIF4E-dosage-sensitive mRNAs that are critical for immune cell function. Lastly, I will investigate whether female patients achieve better therapeutic responses to eIF4E inhibitor.

These studies will establish the first functional link between protein synthesis control and gender disparities in cancer. This proposal will uncover novel subsets of transcripts that are regulated by key translation factors in immune cells, thereby providing a completely new metric for understanding and predicting which bursts of gene expression propagated by translational control drive tumor development. With anticancer agents targeting eIF4E currently in clinical trials and available in our lab, this study holds great promise for treating human cancer by modulating the TME proteome.

Control of Anti-Tumor Response by the Modulation of Neurotransmitter-Expressing Immune Cells

Control of Anti-Tumor Response by the Modulation of Neurotransmitter-Expressing Immune Cells

Control of Anti-Tumor Response by the Modulation of Neurotransmitter-Expressing Immune Cells

Didem Cobanoglu, PhD

Co-PI Murat Can Cobanoglu, PhD; Satwik Rajaram, PhD
Mentor James Allison, PhD
Award Type Team Awards
Institution MD Anderson Cancer Center
Donor Support MRF Breakthrough Consortium-Bristol Myers Squibb Young Investigator Research Team Award to Advance the Field of Translational Immuno-Oncology

Description:

Traditional cancer therapy involves surgery, radiotherapy, and chemotherapy. These modalities aim to ablate the tumor, yet generally the disease relapses due to the inefficiencies of the therapy and the ensuing growth of distant and/or resistant micrometastases. Immunotherapy is a new paradigm referring to the reactivation of the immune system by monoclonal antibodies against inhibitory molecules that are expressed on immune cells in the tumor microenvironment (TME). Monoclonal antibodies against CTLA-4, PD-1, and PD-L1 have been approved for clinical use in multiple cancers and can induce long-term, durable immune responses that result in the clearance of tumors. The most important advantage of immunotherapy is that, thanks to the evolving nature of the immune system, a responding patient is often cured of cancer.

This is the first therapy to accomplish such persistent results. Its biggest downside, however, is that a large group of patients do not respond. This observation led to the hypothesis that there are additional inhibitory mechanisms in the tumor and that these need to be addressed to improve the benefit of immunotherapy.

In this study, we propose to modulate neurotransmitters (NT) to enhance the response to immunotherapy. In preliminary data, we show that NTs exist in tumors, and the immune cells have the ability to detect them. It has also been shown in other studies, including our previous work, that NTs suppress immune function. Therefore, connecting these two together, we propose that NTs in tumor suppress immune cells. As a result, we propose that disrupting the production of NTs in the TME and disrupting their sensing by the immune cells can both increase the response to immunotherapy. There are already many FDA-approved drugs to modulate these pathways, therefore any results we find are highly likely to impact clinical care and do so rapidly.