Good News: First extensive immune profiling of sarcomas shows some types may be susceptible to immunotherapy

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Good News at Fred Hutch

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May 4, 2017
Dr. Seth Pollack

“To me, these findings say that there are certain sarcoma subtypes that really lend themselves to the development of checkpoint inhibitor-based strategies,” said Dr. Seth Pollack, who led the research.

Photo by Robert Hood / Fred Hutch News Service

First extensive immune profiling of sarcomas shows some types may be susceptible to immunotherapy

Sarcomas — cancers of the connective tissues like muscles, joints, fat and bone — come in dozens of subtypes. Clinical trial results have been mixed when treating these diverse tumors with immunotherapy, a targeted therapeutic strategy that has success in other cancers.

But now a study by researchers at Fred Hutchinson Cancer Research Center, published May 2 in the journal Cancer, suggests how both existing and emerging immunotherapy treatments could be successful for sarcomas.

Two sarcoma subtypes — leiomyosarcoma and pleomorphic — showed biological characteristics suggesting they are susceptible to an existing immunotherapy approach using checkpoint inhibitors. This treatment works by blocking a protein that keeps immune cells from attacking cancerous cells.

“Checkpoint inhibitors have transformed the standard of care for melanoma and lung cancer, but it’s been tough to make headway in developing immunotherapy strategies for sarcomas,” said Dr. Seth Pollack, a clinical researcher at Fred Hutch and the study’s senior author. “Before this study, we had a feeling based on preliminary data that some of the sarcomas would behave very differently based on the immune response, and these findings suggest that we’re on the right track.”

Sarcomas comprise more than 70 different cancers that can originate anywhere in the body and are usually named after the tissue from which they arise. 

In the most extensive sarcoma immune profiling to date, Pollack and his colleagues examined tumor samples from 81 patients with types of sarcoma that comprise 75 percent of the disease: leiomyosarcoma, pleomorphic sarcoma, synovial sarcoma and liposarcoma. The samples came from patients who had agreed to allow researchers to study their tumors for developing new therapies.

The researchers aimed to identify patterns of immune response in these sarcomas to identify promising targets for therapies. They measured:

  • expression of 760 genes, mainly related to immune function;
  • levels of proteins called PD-1 and PD-L1 on T cells that tumors use as an “off switch” to keep the immune system from attacking cancer cells;
  • the proportion of T cells in tumors, which indicates how successful the immune system is at attacking cancer on its own; and
  • T-cell receptor clonality, which indicates the precision of the T-cell response.

Leiomyosarcoma and pleomorphic sarcomas were the two subtypes that had a greater immune response by nearly all of the measures in the study, which means that they’re more visible to the immune system.

“To me, these findings say that there are certain sarcoma subtypes that really lend themselves to the development of checkpoint inhibitor-based strategies,” Pollack said. Checkpoint inhibitors are immunotherapies that remove the PD-1 “off switch” and essentially allow the immune system to attack cancer more aggressively.

Meanwhile, synovial sarcoma and liposarcoma had low levels of the immune-response markers, suggesting that other immunotherapeutic strategies, such as adoptive T-cell therapies or vaccines, would work better.

“It’s too early to change how doctors will treat patients, but these findings are influencing the design of clinical trials in sarcoma,” Pollack said.

Ultimately, he hopes to expand treatment options for patients with advanced sarcoma who have an estimated survival of 12 to 18 months.

The Sarcoma Alliance for Research through Collaboration, the Sarcoma Foundation for America and the Gilman Sarcoma Foundation funded the research.

— Molly McElroy / Fred Hutch News Service

More than 175 science and health communicators attended the regional workshop for science communicators at Fred Hutch

Fred Hutch recently hosted a first-of-its-kind regional workshop for science communicators; more than 175 science writers, visual designers and others attended to share and learn about compelling storytelling.

Photo by Robert Hood / Fred Hutch News Service

Fred Hutch hosts first-of-its-kind regional conference for science communicators

On April 28, approximately 175 science writers, visual designers, videographers and others in related fields convened at Fred Hutch for the first Pacific Northwest conference aimed at science and health communicators — also known as public information officers, or PIOs — who work for universities or other organizations.

The conference, “Compelling Science Storytelling: A Pacific Northwest Workshop for Science Communicators,” was supported in part by the National Association of Science Writers and organized by a team of science writers from several different Seattle-area research organizations, including the Hutch, the University of Washington Medical Center, Seattle Children’s Research Institute, the Institute for Health Metrics and Evaluation and Kaiser Permanente Washington Health Research Institute, among others. The event was the first Northwest-region science PIO conference, and the second such conference in the U.S. (The first was held in 2014 in Madison, Wisconsin.)

The workshop addressed a wide variety of topics, from amplifying local work on a global stage to best practices in pitching stories to the media.

Attendees included writers and communications professionals primarily from the Seattle area, but also from Portland, Oregon; Vancouver, British Columbia; Salt Lake City, Utah; and Moscow, Idaho.

The day-long event culminated in a keynote talk by Jacqui Banaszynski, a Pulitzer Prize-winning journalist formerly of The Seattle Times who is now the Knight Chair in Editing at the Missouri School of Journalism. She spoke about elements that make science stories true, compelling and meaningful.

Several current and former Fred Hutch Communications & Marketing staff spoke at the event. They included senior media relations specialists Claire Hudson and Molly McElroy, writer/editor Rachel Tompa, editor Linda Dahlstrom (now director of storytelling at Starbucks) and social media/multimedia producer Bo Jungmayer (now in corporate communications at Premera Blue Cross). 

— Rachel Tompa / Fred Hutch News Service

Dr. Taran Gujral

“Our findings are very relevant to the clinic,” said Dr. Taran Gujral, lead author of the new study.

Pathway that regulates organ size may also underlie tumors’ resistance to certain chemotherapy drugs

A molecular pathway that regulates organ size and inhibits tumor development may play a critical role in resistance — or sensitivity — to certain chemotherapy drugs, according to work published recently in Proceedings of the National Academy of Sciences.

Fred Hutch Human Biology Division faculty member Dr. Taran Gujral, with collaborator Dr. Marc Kirschner of Harvard University, discovered a key pathway, triggered by cell crowding that increases pancreatic cancer cells’ resistance to the DNA-damaging drug gemcitabine. Patient-derived tumors that harbored mutations in this pathway were much more sensitive to gemcitabine treatment in laboratory models of pancreatic cancer, suggesting that similar mutations could help identify patients whose tumors will respond best to gemcitabine and similar chemotherapies.     

“Our findings are very relevant to the clinic,” said Gujral. “It’s a case that very nicely shows that in addition to needing new drugs, we need to focus on understanding how the current drugs work and on identifying a patient population that would benefit from a certain therapy.”

The project arose from previous work by Gujral and Kirschner in which they had developed a computational approach to screen cancer cells for molecular targets that would transform them from chemotherapy-resistant to chemotherapy-sensitive. The scientists hoped to apply this approach to shed light on why pancreatic cancer is so drug resistant, even to gemcitabine, the gold standard of treatment.

“There’s no targeted therapy approach to pancreatic cancer,” Gujral said. “We thought we could take pancreatic cancer cells, which do not respond to gemcitabine, and feed them with kinase inhibitors, hoping to identify kinases which would restore the sensitivity. That was the original idea.”

But a survey of pancreatic cancer cell lines in the literature didn’t help Gujral classify specific lines by resistance or sensitivity to gemcitabine. Cell lines that withered in the presence of gemcitabine in some studies easily resisted the drug’s effects in others. Methods of growing cells and measuring resistance also varied widely.

To address gemcitabine resistance cell line by cell line, Gujral developed a kinetic cell-growth assay, in which he plated pancreatic cancer cells so that they covered 10 to 30 percent of the surface area of culture plates. Then he waited a day and added gemcitabine at varying doses. He imaged the cells every few hours until control-cell, or comparison, cultures had grown so that they completely covered the culture plates, a period of time that depended on each cell line’s particular doubling time.

But if Gujral waited just one day — allowing cells to grow until they covered about 50 percent of the available space — before adding gemcitabine, the results flipped, and every cell line tested was drug- resistant. Gujral found that in crowded conditions like those seen in tumors, only about 3 to 5 percent of cells were dividing, down from a high of about 40 percent, which was seen when cells were quickly growing to fill their space.

“We show that all the previous studies are correct,” he said. “The same cell line can be sensitive or resistant depending on context.”

He found, for the first time in pancreatic cancer cells, that increasingly crowded conditions correlated with changes in a molecular tag on a molecule called Yap — and that this altered the molecule’s location within the cell. Cells often use a phosphate tag, which can be attached to or removed from many molecules, to influence the function and even cellular location of specific molecules. Yap, as it happens, moves in and out of the nucleus, the compartment where cells house their DNA, based on whether it carries a phosphate tag.

When Gujral looked inside cells growing in sparse culture, he saw that Yap had no phosphate tag and was in the nucleus. But when cells closely abutted their neighbors in crowded conditions, Yap was tagged and had moved outside the nucleus.

Gujral observed that where Yap accrues within pancreatic tumor cells is directly linked to their ability to resist gemcitabine. When he genetically manipulated pancreatic cancer cells so that Yap could not be tagged and therefore remained in the nucleus regardless of how crowded the cells grew, their resistance to gemcitabine (and similar drugs that also hinder DNA replication) evaporated.

Gujral discovered that as cells grew more cramped and Yap left the nucleus, levels of gemcitabine dropped compared to cells treated with gemcitabine under more spacious conditions. This was because Yap keeps specific genes, involved in pumping drugs out of the cell and in breaking down gemcitabine, turned off. As crowding prompts Yap to leave the nucleus, these genes are turned on and cells are able to jettison the toxic drug. Modifying Yap so that it remains in the nucleus prevents cells from turning on these genes no matter how confined they grow.

Whether Yap carries a phosphate tag and where it is located are controlled by what’s known as the Hippo pathway, a molecular cascade that prevents organs from growing too large. It is named for the central molecule, Hippo, discovered in fruit flies. Mutations that block the Hippo pathway’s function span cancer types, including mesothelioma, small-cell lung cancer and pancreatic cancer.

Gujral and Kirschner suspected that these mutations could be an unappreciated vulnerability. They tested several cancer cell types in culture conditions that encourage tumor cells to form three-dimensional structures that mimic the natural tumor environment better than a flat plate. In these conditions, the researchers found that mutations in genes in the Hippo pathway made each sensitive to gemcitabine. And when Gujral tested their Yap-modified pancreatic cancer cell lines in a mouse model of pancreatic cancer, he found that gemcitabine could cause tumor regression at doses that had no effect on pancreatic cells with a normal Yap molecule.

“Hippo is considered a tumor-suppressor pathway,” said Gujral. “We show that mutations in a tumor- suppressor pathway make cancer cells sensitive to a specific drug. We also show mechanism.”

— Sabrina Richards / Fred Hutch News Service


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