Friday , July 30 2021

Age-related resistance mechanisms revealed as new targets for treatment – ScienceDaily

Age can cause identical cancer cells with the same mutations to behave differently. In animal and laboratory models of melanoma cells, age was the main factor in the response to treatment.

Cancer has long been known as an aging disease, with 60% of cases and 70% of deaths occurring in people over 65. The new findings by researchers at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health, published in September. 4 in. Discovery of cancer and October 23 at Clinical Cancer Research, reveal new common mechanisms in aging that contribute to the spread of melanoma and resistance to treatment.

Melanoma is an aggressive type of skin cancer that affects about 100,000 Americans annually.

In the lab, senior study author Ashani Weeraratna, Ph.D., the first author of the study Gretchen Alicea, Ph.D., and colleagues combined fibroblasts – cells that generate connective tissue and allow skin to recover from injuries – people aged 25 to 35 or 55 to 65 with laboratory-created artificial skin and melanoma cells. The cells with the aged fibroblasts consistently regulated positively a fatty acid transporter known as FATP2 and increased the uptake of fatty acids from the microenvironment in and around the tumor. When exposed to anticancer drugs, melanoma cells cultured with aged fibroblasts resisted cell death, but this rarely occurred in cells cultured with young fibroblasts, the researchers reported.

“Getting too much fat protects melanoma cells during therapy,” explains Weeraratna, EV McCollum Professor and head of the Department of Biochemistry and Molecular Biology at the Bloomberg School of Public Health, a distinguished professor at Bloomberg (cancer biology), a professor oncology and co-director of the cancer invasion and metastasis program at the Kimmel Cancer Center.

The results are based on a 2016 study in Nature, who reported a mouse melanoma model in which the cancer-promoting oncogenes BRAF, PTEN and CDKN2A were deleted to easily develop tumors. The study found that cancer grew best on the skin of young mice, 6 to 8 weeks old, but metastasized from the skin to the lung more easily in older mice, 1 year old or older. The use of drugs to inhibit the BRAF oncogene is a targeted therapy approach used to treat melanoma in the clinic. In the 2016 study, the Weeraratna laboratory showed that targeting the BRAF oncogene was less effective in reducing tumor growth in elderly mice, and a study of patient responses to the BRAF inhibitor corroborated laboratory findings, showing that complete responses occurred with more frequently in underage patients 55

In the current study, Weeraratna and colleagues used new generation inhibitors of this pathway, including drugs directed at two arms of the BRAF pathway, and assessed the impact of simultaneous depletion of FATP2.

In older rats, therapy directed at BRAF alone worked initially, reducing tumor volume, but the tumors returned in 10 to 15 days, the researchers reported. However, when they added a FATP2 inhibitor to targeted therapy, the tumors went away and did not return during the 60-day period they were monitored.

“Age was the determining factor,” says Alicea. “In young models, melanoma cells responded to targeted therapy initially, and targeting FATP2 had no further impact. In older models, melanoma cells did not respond to targeted therapy until we exhausted FATP2, and then the response was dramatic. When FATP2 was depleted, in all old models, the tumors regressed in size completely and did not grow back for more than two months, a significant amount of time in an experiment with mice. “

This was an extremely important finding because Weeraratna says that most animal models of cancer research use young mice, which can mask age-related factors.

“As we are using mouse models in which the genetic components are identical, these studies point to the critical involvement of the surrounding normal cells and tell us that there are more than genes that are causing the cancer,” says Weeraratna.

Weeraratna says the next step is the development of a FATP2 inhibitor that, once proven to be effective, can be administered in combination with targeted therapies to improve treatment responses, especially for older patients. Alicea points out that, although less common, resistance to treatment related to FATP2 can also occur in patients under 55 years of age.

At the Clinical Cancer Research study, Weeraratna, Mitchell Fane, Ph.D., and colleagues evaluated patients’ responses to the anti-angiogenesis drug Avastin. Angiogenesis refers to the blood supply that nourishes tumors and transports cancer cells to other parts of the body to seed metastasis. Anti-angiogenesis drugs, such as Avastin, work by eliminating the blood supply of cancer.

Using data from a previous UK study of 1,343 melanoma patients who received Avastin after surgery, the researchers came back and divided responses to the drug by age.

Angiogenesis increases with age, so Weeraratna expected to see a greater benefit in older patients than in younger patients, but the opposite was true. Patients aged 45 years or older had virtually no benefit from Avastin, and conversely, patients younger than 45 years had a longer progression-free survival.

Avastin blocks the VEGF angiogenesis-promoting gene, so Weeraratna and the team studied age-stratified melanoma samples from the Cancer Genome Atlas database to see what role VEGF was playing among younger and older patients and to find clues to explain why Avastin did not work for older patients. The researchers found that the expression of both VEGF and its associated receptors decreased significantly among elderly patients. Instead, they found that another protein, sFRP2, was driving angiogenesis in patients over 55.

Their findings were supported by studies in mouse models. When the researchers gave the mice an anti-VEGF antibody, it reduced the growth of new blood vessels by almost 50%, but when the sFRP2 protein was administered simultaneously, the anti-VEGF antibody had no effect, confirming that sFRP2 was another driver of angiogenesis.

“Older patients have more angiogenesis, which helps spread cancer, but is driven by sFRP2, not VEGF,” said Fane, a postdoctoral fellow at the Johns Hopkins Bloomberg School of Public Health and co-author of the study with Brett Ecker , MD, and Amanpreet Kaur, Ph.D. The researchers plan to study the antibodies that block sFRP2 as a potential treatment for patients over 55 who do not respond to Avastin.

Both studies, says Weeraratna, make it clear that age is a parameter that must be considered in the development of experiments and clinical trials.

“Cancer treatment is not a one-size-fits-all,” she says. “Our research shows that younger patients may have very different responses to treatment than older patients. Recognizing that a patient’s age can affect response to treatment is critical to providing the best care for all patients.”

Weeraratna is also exploring how age influences treatment resistance among patients with pancreatic cancer.

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