Strategies for overcoming drug resistance in melanoma treatment

Indolium 1: Synthesizing small molecules to fight advanced melanoma

For adaptive cancers, current medical treatments can only do so much. Treatment costs for melanoma reach $3.3 billion dollars each year, yet this cancer remains a dangerous threat. Melanoma is a skin cancer stemming from melanocytes (cells that make melanin) and is highly likely to spread throughout the body if not diagnosed and treated in the disease’s early stages. Common treatments include radiation, immunotherapy, targeted therapy, and chemotherapy. However, long-term results from melanoma treatment are limited because most patients become resistant to inhibitors, such as vemurafenibwithin several months of beginning treatment.

Using molecules to fight melanoma

Motivated to extend the five-year survival rate of melanoma past 27%,  Jack Arbiser, MD, PhD began developing small molecules to fight cancerous melanoma cells. These small molecule drugs are organic compounds with low molecular weights that can pass through cell membranes to reach intracellular targets. His current project involves indolium 1, a molecule that has strong activity against melanoma. Its mechanism of action (MOA) is by inhibiting NADPH oxidase, a family of enzymes elevated in melanoma. 

Doctor examing patient for melanoma

Arbiser believes indolium 1 may be clinically useful when patients become resistant to mitogen-activated protein kinase (MAPKs) inhibitors, the standard treatment for melanoma. An additional possibility is the use of an indolium 1 therapeutic in combination with current initial treatments to prevent the development of resistance. “There is not going to be one silver bullet that kills a tumor,” says Arbiser, but the interactions of a group of drugs may be the most viable form of long-term treatment.

When developing small molecules for the treatment of cancer and inflammatory diseases, the first step is to identify the molecule. In this case, the research journey began with gentian violet, “a triphenylmethane dye with anti-bacterial, anti-fungal...and anti-tumor properties.” Next, Arbiser’s team synthesized derivatives of their starting molecule. They discovered that a double ringed molecule like indolium 1 was a perfect compromise between single and triple rings. After its success blocking myeloma in cells and mice models, Arbiser thinks a company could take it to market it right now. 
Mark Coburn, the director of licensing at OTT, notes, "In the relentless battle against melanoma, where existing treatments face the formidable challenge of resistance, the groundbreaking research led by Dr. Jack Arbiser and his team at Emory University unveils a beacon of hope for those facing the formidable challenge of this deadliest form of skin cancer.”

Applying indolium 1 in a real-world setting

Melanoma graphic

As both a researcher and clinician, Arbiser works with a multidisciplinary team including chemists, radiation technicians, nurses, and surgical oncologists. While it may be difficult to balance his experiments and his patients, Arbiser noted that “it's ultimately rewarding because you have the possibility of discovering something in your lab and then being the advocate for it.”
Scientists across disciplines dream of saying they cured cancer, but Arbiser recognizes that for now, “if you give somebody ten extra years, that's ten more years for new treatments to come out.” He is looking to give his patients that extra “10, 15, or 20 years” and believes that his shockingly blue molecule indolium 1 has the potential to make that happen. 

- Masin Kearney

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