Melanoma Treatment - New Investigational Drug Shows Promise in Early Phase I Clinical Trials

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Highlights:

• Novel investigational drug dubbed MK-8353 has been developed to block signals such as ERK (Extracellular Signal-Regulated Kinase) pathway, shown to aid cancer cell growth in resistant melanoma
• Advanced melanoma is aggressive skin cancer and resistance to current therapies makes treatment challenging

New investigational compound MK-8353 shows promise in the treatment of advanced melanoma in early phase clinical trials, according to a group of scientists at University of North Carolina (UNC) Lineberger Comprehensive Cancer Center and other institutions. The findings of the current study undertaken by UNC Lineberger's Stergios Moschos, MD, and his colleagues appear in the journal JCI Insight..

The early phase I clinical study involved determining the role of the investigational drug MK-8353 in 26 patients with mutations in BRAF and RAS genes. This drug was developed to block cancer growth and resistance promoting signals such as ERK (Extracellular Signal-Regulated Kinase) in melanomas and other cancers resistant to treatment.

Reason for Current Study - To Overcome Resistance to Current Treatments

Currently, targeted therapy is approved for advanced melanoma and lung cancer with mutations in the BRAF gene that promote cancer growth and spread, but many of the patients develop resistance and the cancer returns sooner than later.

‘MK-8353 compound inhibits ERK (Extracellular Signal-Regulated Kinase) pathway believed to play a role in growth and spread of resistant melanoma’

To overcome this resistance, the study team at UNC Lineberger and other institutions developed the MK-8353 compound to try and inhibit signals that help drive resistance, such as a ERK rather than the early signals that initially trigger the hyperactive growth.

Key Observations of the Study

• Three of the 15 patients showed results consistent to partial responses to the new investigational drug.

Although the study included only a few participants, the study team believe that the responses are similar to studies evaluating Mitogen-activated protein kinase kinase (MEK) inhibitors that block the MEK pathway overactive in certain cancers.

• The low response rates suggest that combination therapies with the new compound MK-8353 might be more effective

"The response rate that we saw for ERK inhibitors is reminiscent of the response seen with MEK inhibitors," said Moschos, who is an associate professor in the UNC School of Medicine. "We think, therefore, that ERK inhibitors cannot be given as single agents, just like MEK inhibitors. The question is: Which combination is best?"

• While trying to establish the safe dose of this drug, the team found that most patients could tolerate treatment up to 400 milligrams twice daily

Due to the occurrence of toxicities, Moschos feels further studies trialing alternative dosing schedules such as once a day regimen or twice a day dose every few days need to be conducted.

"This alternative approach may balance higher, though more temporal, suppression of pERK at the tumor tissue in favor of sparing sustained suppression of ERK signaling in normal tissues," the researchers reported.

Future Studies Planned

• UNC Lineberger's Channing Der, PhD, Sarah Graham Kenan Distinguished Professor in the UNC School of Medicine Department of Pharmacology, has begun work on preclinical studies designed to identify possible drug combinations that would improve ERK inhibitor anti-tumor activity and minimize toxicity for patients.
• Based on a promising combination identified, another phase I clinical trial study led by UNC Lineberger's Autumn McRee, MD, associate professor in the UNC School of Medicine, aims to study an alternative investigational ERK inhibitor combination in pancreatic cancer patients.

"ERK certainly stimulates factors that promote cancer growth," Der said. "ERK is very complex, and it's still surprisingly poorly understood, but what is very clear is that it is required for cancer growth and that's why there are a number of inhibitors in this pathway that are either approved, or under clinical evaluation. Clearly, drug companies for good reason have decided that this is an important pathway, let's make inhibitors against it."

In conclusion, a lot of recent interest generated in the ERK pathways role in cancer growth and resistance has spurred a series of studies to develop safe and effective ERK inhibitors targeting this pathway. Whether they will live up to expectations, only time will tell.

References:

1. Treatment of Metastatic Melonoma: A new World Opens - (https:www.skincancer.org/skin-cancer-information/melanoma/melanoma-treatments/treatment-of-metastatic-melanoma)
2. MEK inhibitor - (https:en.wikipedia.org/wiki/MEK_inhibitor)

Source: Medindia

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