Flip the Switch 01-29

Changes in fat metabolism may promote prostate cancer metastasis...

Prostate tumors tend to be what scientists call “indolent”—so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, the disease is invariably fatal.

In a set of papers published in the journals Nature Genetics and Nature Communications, researchers at Harvard Medical School and the Cancer Center at Beth Israel Deaconess Medical Center have shed new light on the genetic mechanisms that promote metastasis in a mouse model and implicated the typical Western high-fat diet as a key environmental factor driving metastasis.

“Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has been lacking,” said first author Ming Chen, HMS research fellow in medicine in the laboratory of Pier Paolo Pandolfi, the HMS George C. Reisman Professor of Medicine at Beth Israel Deaconess.

Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including prostate cancer are much higher in the United States than in nations where lower fat diets are more common. While prostate cancer affects about 10 percent of men in Asian nations, that rate climbs to about 40 percent when they immigrate to the U.S., mirroring the rates among the native-born U.S. population. That points to an environmental culprit that may work in concert with genetic factors to drive this aggressive, fatal disease.

“The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients,” said senior author Pandolfi, who is also director of the Cancer Center and the Cancer Research Institute at Beth Israel Deaconess. “Our data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and we also demonstrated how environmental factors can boost these mechanisms to promote progression from primary to advanced metastatic cancer.”

The tumor suppressor gene PTEN is known to play a major role in prostate cancer; its partial loss occurs in up to 70 percent of primary prostate tumors. Its complete loss is linked to metastatic prostate disease, but animal studies suggest the loss of PTEN alone is not enough to trigger progression. Pandolfi and colleagues sought to identify an additional tumor suppressing gene or pathway that may work in concert with PTEN to drive metastasis.

Looking at recent genomic data, Pandolfi and colleagues noticed that another tumor suppressor gene, PML, tended to be present in localized (nonmetastatic) prostate tumors but was absent in about a third of metastatic prostate tumors. Moreover, about 20 percent of metastatic prostate tumors lack both PML and PTEN.

When they compared the two types of tumor—the localized ones lacking only the PTEN gene versus the metastatic tumors lacking both genes—the researchers found that the metastatic tumors produced huge amounts of lipids, or fats. In tumors that lacked both PTEN and PML tumor suppressing genes, the cells’ fat-production machinery was running amok.

“It was as though we’d found the tumors’ lipogenic, or fat production, switch,” said Pandolfi. “The implication is, if there’s a switch, maybe there’s a drug with which we can block this switch and maybe we can prevent metastasis or even cure metastatic prostate cancer,” he added.

Such a drug already exists. Discovered in 2009, a molecule named “fatostatin” is currently being investigated for the treatment of obesity. Pandolfi and colleagues tested the molecule in lab mice.

“The obesity drug blocked the lipogenesis fantastically, and the tumors regressed and didn’t metastasize.”

In addition to opening the door to new treatment for metastatic prostate cancer, these findings also helped solve a long-standing scientific puzzle. For years, researchers had difficulty modeling metastatic prostate cancer in mice, making it hard to study the disease in the lab. Some speculated that mice simply weren’t a good model for this particular disease. But the lipid-production finding raised a question in Pandolfi’s mind.

“I asked, ‘What do our mice eat?’” Pandolfi recalled.

It turned out the mice ate a vegetable-based chow, essentially a low-fat vegan diet that bore little resemblance to that of the average American male. When Pandolfi and colleagues increased the levels of saturated fats, the kind found in fast food cheeseburgers and fries, in the animals’ diet, the mice developed aggressive, metastatic tumors.

The findings could result in more accurate and predictive mouse models for metastatic prostate cancer, which in turn could accelerate discovery of better therapies for the disease. Additionally, physicians could soon be able to screen their early-stage prostate cancer patients for those whose tumors lack both PTEN and PML tumor suppressing genes, putting them at increased risk for progressing to metastatic disease. These patients may be helped by starving these tumors of fat either with the fat-blocking drug or through diet.

“The data are tremendously actionable, and they surely will convince you to change your lifestyle,” Pandolfi said.

This work was supported by a U.S. Department of Defense Prostate Cancer Research Program Postdoctoral Training Award and the National Institutes of Health (grants R01 CA142784, R35 CA197529, P01 CA120964 and R35 CA197459.)

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Cracking Tumor Defiance 01-18

Why does immunotherapy achieve dramatic results in some cancer patients but fail in others? 

Scientists have elucidated the mechanism behind some tumor's ability to escape immunotherapy drugs. Image: iStock


Why does immunotherapy achieve dramatic results in some cancer patients but doesn’t help others? It is
an urgent and vexing question for many cancer specialists.

Now, two research groups from Harvard Medical School based at Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.

The findings, the researchers say, reveal potential new drug targets and could aid efforts to extend the benefits of immunotherapy treatment to more patients and target additional types of cancer.

The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2, PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins. 

Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell carcinoma (ccRCC) gain clinical benefit—sometimes durable—from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.

The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive tumor antigens called, neoantigens, which help the patient’s immune system recognize and attack tumors and make the cancer cells’ microenvironment hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.

To search for other characteristics of ccRCC tumors that influence immunotherapy response or resistance, the researchers used whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analyzed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.

When the data were sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumors lacked a functioning PRBM1 gene. About 41 percent of patients with ccRCC kidney cancer have a nonfunctioning PBRM1 gene. That gene encodes a protein called BAF180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodeling complex. 

Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, including those in the gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.

The finding does not directly lead to a test for immunotherapy response yet, the scientists caution, but they carry a clear therapeutic promise.

“We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations,” Choueiri said.

In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 tool to sift the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells. 

The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodeling complex—the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells—as being involved in resistance to immune T cells.

When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors noted, “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack.” Finding ways to alter those target molecules, they added, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”

Research included in the report by Van Allen and Choueiri was supported by Bristol-Myers Squibb, American Association for Cancer Research Kure It Research Grant for Immunotherapy in Kidney Cancer, Kidney SPORE, and Cancer Immunologic Data Commons (National Institutes of Health grant U24CA224316).

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