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Mass General Hospital Gets Funding to Sequence Rare Melanoma Subtypes, Hunt for Novel Drug Targets


NEW YORK – Massachusetts General Hospital researchers are working to identify druggable targets that will enable precision treatment of mucosal and acral melanomas, two rare subtypes of the disease that have no targeted therapy options.

The three-year research project received a $900,000 grant from the Melanoma Research Alliance last week and will be led by Genevieve Boland, director of the melanoma surgery program at the Massachusetts General Hospital; Liron Bar-Peled, assistant professor of medicine at Massachusetts General Hospital Cancer Center; and Nir Hacohen, director of the Massachusetts General Hospital Center for Cancer Immunotherapy.

Boland and colleagues at her lab at MGH have been putting into a repository tumor tissue and blood samples collected from melanoma patients. The grant will fund a three-part sequencing project focused on melanoma types where there is an unmet need, and using the data, researchers hope to identify and validate druggable targets and find new treatments for patients.

Mucosal melanomas are found not on the skin but inside the body. These tumors can occur on mucous membranes of the body including the mouth, nose, sinuses, anus, vulva, vagina, penis, or gastrointestinal tract. Acral melanomas occur on "plantar surfaces," Boland said, including the palms of the hands and soles of the feet.

Previous research has found that mucosal and acral melanomas are distinct from cutaneous melanoma, Boland said. Only about 15 percent of mucosal melanoma tumors will have a c-KIT mutation that can be targeted with KIT inhibitors, though acral melanomas are "even less well characterized," she said.

Meanwhile, about half of cutaneous melanomas, for example, have a BRAF V600 mutation. There are several targeted therapies approved in the US to treat BRAF V600-mutated melanoma, including Pfizer's combination Braftovi (encorafenib) and Mektovi (binimetinib), Novartis' combo Tafinlar (dabrafenib) plus Mekinist (trametinib), and Genentech's Zelboraf (vemurafenib) and Cotellic (cobimetinib).

Physicians also use immunotherapies to treat mucosal and acral melanoma subtypes, but even then the response rates are much lower than for cutaneous melanomas.

Moreover, these less well-characterized subtypes tend to show up in minority patients who are often left out of clinical trials. "Both of these non-cutaneous melanoma subtypes are enriched in non-Caucasians, and mucosals are seen quite commonly in women, and they are biologically distinct from cutaneous melanoma," Boland said. "Not only are these melanomas understudied, but they are not as responsive to the standard therapies we use for metastatic cutaneous melanoma."

The first part of the recently funded project will use cysteine druggability mapping, through Bar-Peled's lab, to identify druggable cysteines in proteins that were previously thought undruggable. The researchers will compare the targets found in mucosal and acral melanomas to those identified in cutaneous melanoma to flag any shared targets or novel targets that could benefit these subsets of patients.

The researchers will then validate the targets identified in the first stage of the project by sequencing the mucosal and acral melanoma samples in the tumor bank established by Boland's lab. Her lab has the capability to conduct single-cell RNA-seq, multiplex imaging, and spatial transcriptomics.

Once potential targets are identified and researchers confirm they are expressed in these tumors, they will then move into mouse model testing to validate that the target is druggable and look for off-target effects. Boland noted that the team is starting this project with a gene identified from earlier research, SOX10, which regulates the proliferation, survival and melanogenesis of melanocytes.

"We've been able to show that SOX10 is an upstream driver of the melanocytic fate, and it is expressed not only in cutaneous melanoma, but in these other relevant subtypes," Boland said. "We want to further develop some of the approaches to SOX10 targeting."

This research is corroborated by preclinical data published this year in Nature Communications, which showed that loss of SOX10 makes cutaneous melanoma cells resistant to BRAF inhibitors and MEK inhibitors. However, researchers from Sidney Kimmel Cancer Center and elsewhere, further showed that cIAP1/2 inhibitors could potentially eliminate these resistant cells with SOX10 loss and when combined with BRAF/MEK inhibitors could be a way to make refractory cutaneous melanoma patients responsive again.

Additionally, a preclinical study published last year by researchers at the Medical University of Warsaw in Poland showed that therapeutic targeting of SOX10 and VEGF in melanoma mouse models inhibited tumor growth and slowed angiogenesis or the formation of new blood vessels in tumors.

Rare tumors are already hard to study due to their infrequency in the population, but researching these melanoma subtypes have additional challenges. Because mucosal melanoma can occur in several regions of the body, patients will often come through different oncology specialties including head and neck, gynecological, or gastrointestinal departments.

To collect tissue for the tumor bank, Boland's lab has had to develop relationships with colleagues in other specialties at Mass General to identify as many patients with these melanoma subtypes as possible. She also has worked with researchers around the world to get a better understanding of these rare tumors, because both mucosal and acral melanoma are more common in Asia.

"That's one challenge that, within our institution, we've been fairly successful at addressing, so that we're not missing these patients that come through Mass General," Boland said.

While the project is just getting underway, Boland hopes that the team will be able to nominate and validate new targets for these subtypes by the end of the three-year effort. Once those are identified, she hopes they will then be able to begin actually developing personalized drugs to treat these cancers.

"We've been optimizing this process using cutaneous melanoma samples just to make sure that the pipeline is working, and we are confident that it is," she said. "Now we're going to start shifting that emphasis to the high-throughput analysis with these other melanoma subtypes. We've been doing this, but this grant will certainly [help us] pick up the pace and light the fire behind our efforts in these other melanoma subtypes."