Researchers have found that studying the landscape of DNA and RNA alterations across multiple organs of metastasis may provide a new direction in cancer therapeutics to address treatment failure, according to a new study published by Liu et al in Nature Medicine. The new findings from analyzing genetic changes in the organs of recently deceased patients may help researchers understand how metastatic cutaneous melanoma spreads in those who had initially benefited from precision therapies.
Background
“We hope to reconstruct, from the end of life, the lethal journey melanoma traverses across time and body sites,” explained senior study author Roger Lo, MD, PhD, Professor of Medicine and Molecular and Medical Pharmacology, Associate Chief of Dermatology, and Director of the Dermatology STAR Residency Program at the University of California, Los Angeles David Geffen School of Medicine. “We need to know how many ways—even within the same patient—the cancer evades these powerful therapies, what underlying processes create ‘new species’ capable of escaping therapies, [and] whether the cancer co-opts different organs to help it spread and resist therapies,” he stressed.
Much of what researchers know about cancer and treatment comes from the first point of patient contact—when tumors are newly diagnosed, have not overtly spread in the body, and have not been treated either surgically or with systemic therapy. Much less is known about cancer in patients with metastatic, terminal disease.
Precision therapies targeting cutaneous melanoma are designed to either block the critical cancer growth-and-survival pathway activated by mutations, or reawaken the body’s immune system's T cells.
The researchers focused on two major subtypes of metastatic cutaneous melanoma classified by BRAF and NRAS mutations. Patients whose melanoma harbors a BRAF mutation may receive treatment with either BRAF-targeted therapy or immune checkpoint inhibitors. These are usually initiated one after another, including after the first therapy fails to shrink the tumors or stops working after a period of time. Patients whose melanoma harbors a NRAS mutation—found in about 20% of patients—are only eligible to receive immunotherapy.
Study Methods and Results
In the new study, the researchers used “rapid” or “warm” autopsies—conducted within hours of death in patients who had previously consented to them—to retrieve tumors that had spread to all possible organs of those who had initially benefited from precision therapies developed over the past 10 to 15 years.
“We are taking a much-needed approach to understanding cancer-related death, which usually results after the cancer has spread to distant sites, even after treatment with multiple systemic therapies. These therapies can be highly active initially but lose efficacy over time in a process termed ‘acquired therapy resistance.’ Alternatively, they may not work right from the outset through ‘innate resistance,’” Dr. Lo noted.
He and his colleagues deciphered common-denominator mechanisms by which cancer may become therapy-resistant—thereby providing critical clues to develop new therapeutic strategies. Additionally, the researchers identified the ways in which the metastatic cancer cells may have taken advantage of specific organ environments, pointing to the need for distinct approaches in treating patients with metastatic disease disproportionally affecting one or a few organs.
“The ability of cancers to escape precision treatments results from outgrowth of variant subpopulations that harbor traits allowing them to be impervious to the therapies, sometimes by taking advantage of a particular organ’s environment,” Dr. Lo detailed.
Conclusions
“We analyzed the DNA and RNA landscape from this autopsy cohort and, cognizant of the caveats of cross-study comparisons, singled out salient traits of terminal melanoma that distinguished it from early-stage melanoma and melanoma that had never been treated with either form of therapy,” underscored lead study author Sixue Liu, PhD, a postdoctoral research fellow in the Division of Dermatology at the university of California, Los Angeles David Geffen School of Medicine.
The researchers found that one of the two therapies—which targets the BRAF mutation–activated MAPK pathway—may hold the potential to change the mutational profile of melanoma. Such a shifted mutational signature represents an imprint of DNA-mutagenic processes and/or defective DNA damage repair processes, and may have diagnostic or therapeutic implications.
“Warm autopsies represent a unique, precious, and humbling opportunity that allows for our deceased patients to ‘talk’ and guide next generations of treatments, such that future patients suffer less and live longer. It is clear that end-stage melanoma escapes both types of therapies by evading the immune system,” highlighted co–study author Stergios Moschos, MD, Associate Professor of Medicine in the Division of Oncology at the University of North Carolina at Chapel Hill. “This study puts a sharp focus on alternative strategies to make the cancer visible to our body’s antitumor immune system,” he concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.
