Targeting MC1R in metastatic melanoma

November 26, 2018

In 1960, scientists described the "Philadelphia chromosome" that causes chronic myeloid leukemia, and in 2001 the Food and Drug Administration approved the drug imatinib to disable the action of this cancer-causing genetic change. It was the dawn of genetically-targeted treatments against cancer and it seemed as if many cancers would fall to a similar strategy: Find a genetic difference between cancer cells and healthy cells, and then develop a drug to target this difference. Of course, rarely has it proved that easy. It's difficult to find a genetic difference common to all cells within a single cancer, and many of these differences are impossible to target with existing drug strategies. Often this seemingly simple gene/drug pairing doesn't work.

Then again, sometimes it does.

A University of Colorado Cancer Center study published in the journal Science Translational Medicine describes a genetic change common to 80 percent of human melanomas, the most deadly form of skin cancer, and also describes a molecule that seeks out cells marked by this genetic change. The current study attaches a radioactive label to the targeting molecule and uses positron emission tomography (PET) imaging to show that the radiolabeled molecule does, in fact, seek out and bind to melanoma cells. Using a similar approach, it may be possible to not only image these cells, but to attach therapy to this targeting molecule to kill these melanoma cells.

The work starts with a protein called melanocortin-1 receptor (MC1R), which is involved in determining skin and hair color, but which is also found at a higher level on the surface of more than 80 percent of human melanomas. The current study describes a "peptide" that specifically binds to MC1R. If MC1R is a lock, then the peptide 68Ga-DOTA-GGNle-CycMSHhex is the key that fits it. In this case, researchers attached an imaging radionuclide to this peptide - the combination of peptide and radionuclide found, bound, and "lit up" melanoma metastases, allowing researchers to image these melanoma cells.

The success of this molecular targeting approach suggests the possibility of using the peptide as a delivery vehicle to transport a therapeutic radionuclide directly to melanoma cells marked with MC1Rs for therapy.

"Basically, we attach the imaging radionuclide to the peptide, then the radiolabeled peptide finds MC1Rs on the melanoma through blood circulation, allowing us to use a PET machine to gather the signals from the radiolabeled peptide for melanoma imaging. It's a very sensitive way to see melanoma," says Yubin Miao, PhD, investigator at CU Cancer Center and Director of Radiopharmaceutical Science at the Radiology of CU School of Medicine.

In addition, researchers were able to replace the radiolabel with a fluorescent one to generate a new MC1R-targeting fluorescence imaging probe (called Cy5.5-GGNle-CycMSHhex). The current study shows that the fluorescent probe binds and stains MC1Rs on melanoma cells and lesions. Miao sees that the combination of these two approaches - one radiolabeled and one fluorescent - may potentially improve surgical outcomes for melanoma via imaging-guided surgery.

He also sees the potential to use a similar strategy as a personalized therapeutic approach for patients with melanoma metastases high in MC1Rs, especially for brain metastases.

"Approximately 60 percent of patients with metastatic melanoma develop brain metastases during the course of their disease. Patients with brain metastases have much shorter life expectancies than patients without brain metastases. Our study shows that the MC1R continues to mark melanoma cells even after these cells metastasize from the site of origin to brain, and this peptide can bind to MC1Rs in melanoma brain metastases. One potential application for this technology is to use our imaging systems to identify MC1R-postive melanoma tumors and then treat these lesions with therapies delivered by this peptide," Miao says.

For now, the current study demonstrates the first-in-human ability to image melanoma metastases using the group's radiolabeled peptide. With more funding and collaboration, the Miao group hopes to explore the therapeutic potential in the near future.
-end-


University of Colorado Anschutz Medical Campus

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.