NEW YORK—While melanoma is not the most common form of cancer—that distinction belongs to breast or lung cancer—it remains one of the most aggressive and deadly forms of skin cancer. Melanoma accounts for just 1 percent of skin cancers, according to the American Cancer Society, but incidence rates have been on the rise for the past 30 years. The society reports that 87,110 new melanoma cases were expected to be diagnosed in 2017, with 9,730 deaths attributed to this cancer type.
Though a variety of treatment options exist, from resection surgery to chemotherapy, melanoma’s tendency to metastasize and spread rapidly means that there is always room for new and more effective therapies.
A study led by Mount Sinai scientists might have a new target for such therapies—or rather, two targets: a gene called AMIGO2 and its partner gene, PTK7. Prior to this study, little was known about the role either gene plays in cancer, but now it has been discovered that both are required for melanoma cells to grow and spread. The study in question was published in Molecular Cell.
“Melanoma is the most aggressive form of skin cancer, affecting more and more patients,” said Dr. Emily Bernstein, senior author of the study and associate professor of oncological sciences and dermatology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “While immunotherapy and targeted therapies have significantly improved the outcome for some metastatic melanoma patients, they have had success in a small subset of patients and can cause significant toxic side effects. Thus, their limitations underscore the need for new therapies, highlighting the importance of this research’s discovery of novel targets.”
AMIGO2 is “a member of the Amphoterin-induced gene and ORF family,” the Molecular Cell paper notes. Additionally, the gene was recently reported to be “a pro-survival factor in endothelial cells subjected to hypoxia, thus playing a key role in the vasculature.” As cancer cells exist in hypoxic environments and often trigger angiogenesis to bring more blood flow to tumors, a target linked to hypoxia is promising for cancer treatment.
This revelation came about thanks to the team’s study of bromodomain and extraterminal (BET) proteins, which regulate AMIGO2 and gene expression in cancer. As reported in the paper, “Our groups and others reported that BRD2 and BRD4 [members of the BET family] are overexpressed in melanoma tissues and are essential for tumor maintenance. Silencing of BRD2 and BRD4, as well as BET inhibition, impairs melanoma growth, suggesting that BETs regulate pro-proliferative and/or survival genes.”
Based on these results, the team performed a loss-of-function screen in a subset of genes “that are significantly upregulated relative to normal human melanocytes, in order to identify melanoma pro-tumorigenic factors,” the authors noted in the paper. That led them to discovering AMIGO2 and its upregulation in melanoma cells, while mass spectrometry let them identify PTK7 as also being necessary for melanoma survival.
As melanoma develops, AMIGO2 levels increase; by silencing the function of AMIGO2, cancer growth is notably slowed. As AMIGO2 regulates PTK7 function, which also plays a role in melanoma cells’ growth and survival, inhibiting AMIGO2 has double the impact in inhibiting cancer growth, so to speak. Both genes are located on the membrane of melanoma cells.
“We assessed AMIGO2 expression by qRT-PCR in a panel of melanoma cell lines and [normal human melanocytes] and found that AMIGO2 is higher in more melanomas irrespective of genotype. AMIGO2 is also upregulated at the mRNA and protein levels in patient-derived melanoma short-term cultures,” the authors wrote.
“Our data indicate that AMIGO2 is sensitive to [BET inhibitors], displays increased expression in melanoma tissues and acquires BET-regulated [super-enhancers] in melanoma … Our study further illustrates the value of leveraging the BETi-associated transcriptome as an effective strategy to identify pro-tumorigenic genes and therapeutic targets in melanoma,” they continued.
Fortunately, some work has already been done in exploring PTK7 as a drug target: therapies against this gene—specifically, antibody-drug conjugates (ADC)—have already undergone successful Phase 1 testing in clinical trials of solid tumors. The results were reported in a Science Translational Medicine paper published in January 2017, titled “A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.” When testing their PTK7-targeted ADC against patient-derived xenografts, mouse models of triple-negative breast cancer, ovarian cancer and non-small cell lung cancer, the ADC “induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of [tumor-initiating cells].”