'Basic Science of Sarcomas' fascinates

By Suzie Siegel

As a patient who last took biology 40 years ago, much of what was presented at the American Association for Cancer Research’s “Basic Science of Sarcomas” conference flew over my head. But even if you and I don’t know what a TLR4 agonist GLA-SE is, I hope you can get a sense of the ways doctors and scientists are working on better treatments for sarcoma.

Michael Dyer, PhD

At the first AACR conference on sarcoma this fall, the first presentation was by Michael Dyer, PhD, of St. Jude Children’s Research Hospital in Memphis. In 2013, he helped launch the Childhood Solid Tumor Network, which “offers the world's largest and most comprehensive collection of scientific resources for researchers studying pediatric solid tumors and related biology,” according to its website. It shares resources with other researchers without asking for credit, and shares its data with drug companies.

Dr. Dyer used mice with a piece of human Ewing sarcoma grafted onto them (“xenografts”). He gave them a PARP inhibitor with the drugs irinotecan and temozolamide. Increasing the dose of irinotecan made the combination much more effective.

“Irinotecan has been around for a million years,” Kurt Weiss, MD, of the University of Pittsburgh Medical Center, said later. “Combination therapy is going to be huge. If we had not one more drug developed, we’d be fine. We need to use drugs smarter.”

Testing drug combinations takes time, money and the cooperation of the companies that own the different drugs. As researchers learn more about the biology of different cancers, they are making better guesses of what combinations will work.

Karen Cichowski, PhD

Karen Cichowski, PhD, of Brigham and Women’s Hospital in Boston, discussed a phase 2 trial that found selumetinib alone was not effective against soft-tissue sarcoma, but did show activity against leiomyosarcoma when combined with temsirolimus. The dosage of temsirolimus was reduced to lessen the side effects.

She taught us that researchers may not grasp how harsh drugs will be on humans, just by trying them in mice first.

Dr. Cichowski is also working on adding an mTOR inhibitor to either HDAC or HSP90 inhibitors for malignant peripheral nerve sheath tumors.  

Elaine Mardis, PhD

For genomic testing, doctors cannot just collect DNA from a tumor, said Elaine Mardis, PhD, co-director of the Genome Institute at Washington University in St. Louis. They also need RNA as well as a sample of normal tissue for comparison. But such a comprehensive study cannot guarantee a doctor will find a way to treat the person’s cancer, she noted. A drug may not be available or sufficient by itself. Dr. Mardis, who is on the AACR board, works on The Cancer Genome Atlas (TCGA) sarcoma project. All the results are made public for others to use.

Cancer gobbles up more glucose than does normal tissue. The trick is to starve the tumor, but not other cells. “The brain needs glucose, too,” said Matthew Vander Heiden, MD, PhD, of the Massachusetts Institute of Technology in Cambridge. His lab looks at the metabolism of cancer cells, with the realization that the tumor environment and tumor cell of origin make a difference. The metabolism of leiomyosarcoma of the kidney, for example, will differ from a bone sarcoma, he said.

Brian Van Tine, MD, PhD

Synovial sarcoma cells are "unusually addicted to glucose" and die quickly when deprived of it, said Brian Van Tine, MD, PhD, of Washington University in St. Louis. He bought the anabolic steroid DHEA to alter glucose biology and tried it on xenografted mice. He hopes to open a clinical trial with pharmaceutical-grade DHEA.

Rama Khokha, PhD, of the Prince Margaret Cancer Centre in Toronto, said a study of RANKL signaling in osteosarcoma led to a phase 2 clinical trial for denosumab. She helped develop Lentihop, a technology that uses lentiviruses to inject normal cells with elements to turn them into cancer. The process can help identify cancer genes and pathways.  She is offering the tech to others.

Cigall Kadoch, PhD

Cigall Kadoch, PhD, of Dana-Farber Cancer Institute in Boston, discussed her work to develop treatment for cancers, such as synovial sarcoma, that are driven by BAF complex alteration.

Research on an LSD1 inhibitor for Ewing sarcoma led to the drug SP-2577, said Stephen Lessnick, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio. “This is a very, very encouraging molecule in pre-clinical development.”  

Pancras Hogendoorn, MD, PhD, of Leiden University in the Netherlands, also studies Ewing. By using zebrafish, he can see a 3-D image of a tumor in a living animal.

The number of possible combinations of immune therapy drugs outnumber sarcoma patients, and collaboration will be needed to figure out what works, said Robert Maki, MD, PhD, of Mount Sinai Medical Center in New York. With 70+ subtypes of sarcoma, he wondered whether researchers will focus on the biology first or look at patients who have exceptional responses.

A promising sign is the recent announcement by some of the companies with immunotherapy drugs that they are working with one another on combinations. 

Karolina Palucka, MD, PhD

We might not need to determine all the mutations of a cancer if we could turn on the dendritic cells in and around it, said Karolina Palucka, MD, PhD, of the Jackson Laboratory for Genomic Medicine in Farmington, Conn. But, she warned, doctors need to be careful in injecting a vaccine into a tumor because it could affect cells throughout the body.

Seth Pollack, MD

Macrophage and checkpoint inhibitors combined may be important for leiomyosarcoma, said Seth Pollack, MD, of the Fred Hutchinson Cancer Research Institute in Seattle. His research also includes a phase 1 trial for TLR4 agonist GLA-SE and radiation therapy for metastatic sarcoma.

David Langenau, PhD, of Harvard, described how NOTCH/SNAI1 inhibition may help children whose embryonal rhabdomyosarcoma has returned.

The Pax3:Foxo1 fusion gene can cause chemotherapy to fail in some children with alveolar rhabdomyosarcoma, said Charles Keller, MD, of the Children’s Cancer Therapy Development Institute of Beaverton, Ore. His team is researching whether the addition of the HDAC inhibitor entinostat to chemo will make it more effective.  

Questions? Ask them in the comment section; I’ll answer them the best that I can.

Collaborating for a moonshot on cancer

By Suzie Siegel

What can patients do to help the new federal “moonshot” cure cancers? “Demand collaboration from the scientific community,” Vice President Joe Biden, in charge of the project, said last week.

I’m happy to report that collaboration was evident at international meetings on sarcoma last fall in Salt Lake City. What stood out to me was synergy, whether it was drug combinations or people working together to be more effective.

The Connective Tissue Oncology Society (CTOS) celebrated its 20th anniversary with 750 doctors, scientists, students, advocates and other health-care professionals from around the world – more than expected.

The Sarcoma Alliance for Research through Collaboration (SARC) held its biannual meeting in conjunction with CTOS, as usual. For the first time, the American Association for Cancer Research (AACR) put on a conference on the “Basic Science of Sarcomas,” and nurses from the Oslo University Hospital in Norway had a symposium for their colleagues.

Dr. Jonathan Fletcher

The AACR conference grew out of a group of about 35 doctors, mostly men, who began meeting privately before CTOS to discuss cutting-edge sarcoma science, said Jonathan Fletcher, MD, of Brigham and Women’s Hospital in Boston. As the years passed, they wanted to open the meeting to others, especially younger doctors. This fall’s conference attracted 228 people, more than expected.

"We're thrilled to see this expansion," said Dr. Fletcher, one of the conference organizers. Everyone with whom I spoke raved about the conference.

Dr. Herman Suit

The CTOS meeting began by honoring Herman Suit, MD, its founding father. In the early 1950s, he said, each discipline was for itself and waged verbal combat. At England’s Oxford University, he was delighted to find it multidisciplinary and collaborative.

That is now the norm, except for a few people who have this “big Y chromosome problem,” said Dr. Suit, a professor emeritus of radiation oncology at Harvard Medical School in Cambridge, Mass.

In 1993, a patient funded a meeting of sarcoma oncologists. Afterward, Dr. Suit suggested the doctors meet regularly. They thought of merging with the Musculoskeletal Tumor Society, but its members had to be surgeons.  In 1995, they founded CTOS.

In my next post, I’ll highlight the AACR presentations.

Could changes in the use of tissue hurt research?

By Suzie Siegel

Proposed changes to the use of blood and tissue will greatly hurt sarcoma research, some pathologists say.

For four years, 16 federal agencies have worked on changes to the Common Rule on the ethics of research on human subjects. Comments have been sought along the way, but Wednesday's deadline is fast approaching. (This link details the changes and allows people to comment.)
 
In general, health-care workers remove blood and tissue from patients to treat them or to do research. If done for research, the project has to be explained and patients have to give written permission. This is called informed consent.

Dr. Jerad Gardner

Patients also give permission for procedures to diagnose and treat them. Leftover blood and tissue may be preserved and stored (a k a “archived” or “banked”) in case they need to be reviewed or tested later to help the patient, said Jerad M. Gardner, MD, assistant professor of pathology and dermatology at the University of Arkansas in Little Rock.

Although these biospecimens weren’t taken for research, current rules allow doctors and scientists to use them for research without patients’ consent if all identifiable information is removed. This is called deidentifying.

Under the proposed changes to the Common Rule, specimens now in storage could be used for research without patients’ permission if deidentified. In the future, however, patients would have to sign a form saying specimens could be used in whatever projects might arise. The health-care system would have three years to comply.

In an article Dec. 10 in the New England Journal of Medicine, the director and deputy director of the National Institutes of Health wrote that many patients want to decide if their blood and tissue can be used for research. “In the beginning, there will be additional costs and effort needed to make the consent process work and to track the consent status of stored biospecimens,” the article says. “Enormous benefits, however, will be realized as biospecimens become more available for secondary research.”

Dr. Brian Rubin

Some sarcoma pathologists disagree. “The proposed changes are unnecessary and overreaching,” said Brian Rubin, MD, PhD, director of Soft Tissue Pathology at the Cleveland Clinic. “While they are well-intentioned, they lack any knowledge of research practices in the USA. They will only inhibit research, not facilitate it, and they will not help patients in any way.”

“While we fully agree that privacy concerns need to be addressed, we think that the proposed changes go too far,” wrote Matthew van de Rijn, MD, PhD, a pathology professor at Stanford University in California, and Alex Lazar, MD, PhD, director of the Soft Tissue Pathology Fellowship Training Program at M.D. Anderson Cancer Center in Houston, in a letter to patient advocates in October.

They urged us to oppose the changes, citing the opinion of William Grizzle, MD, PhD, head of the Pathology Program for Translational Research in Neoplasia at the University of Alabama in Birmingham.  (I’ve written before on the importance of tissue banks.)

“Using these old tissues for research gives us a priceless opportunity to better understand rare diseases while causing essentially no real risk to any of these patients from whom the tissues were obtained,” Dr. Gardner said. “Institutional review boards (IRBs) and other research ethics authorities have long recognized this potential for large benefit but extremely low risk, which is why studies of this sort are often approved by the IRB without any need for additional consent.”

The Dec. 10 article cited a famous case in which cancer cells removed from a woman without her consent have been widely used in research.

“I loved Rebecca Skloot's book about Henrietta Lacks,” Dr. Gardner said. “It certainly made me think about who owns tissue. Her story is very different because extra tissue was taken from her during an operation solely for the purpose of research without her permission. It would be like intentionally taking blood from you just to do research but not telling you about it.

“Compare that to the archival pathology research we do now, which would be like if you had blood drawn to check your cholesterol level and then instead of throwing the leftover blood away, we used it for research. It may seem subtle, but it's different in my opinion. The intention of why the tissue/blood sample was removed is the key. If purely for research, you must get consent. If it was removed with permission for diagnosis or patient care, and then there is an extra sample that isn't needed, it seems reasonable to be able to use that for research.”

The Dec. 10 article noted that even if tissue is deidentified, molecular testing might still reveal the patient’s identity. A member of the Presidential Commission for the Study of Bioethical Issues wrote:

“Over the past 3 years, technology has advanced rapidly, such that it is now possible to identify the donors of biospecimens, even when samples are stripped of traditionally recognized identifiers. As a result, the deidentification process no longer sufficiently protects biospecimen donors from privacy and security risks.”

“But to put things in perspective,” Dr. Gardner said, “all of this tissue, when it is not being used for research, is stored in filing systems in laboratory storage rooms and can be looked up and accessed by any pathologist in the department at any time. The report with all patient identifiers can be pulled up and reviewed also. This, of course, is so we can access old cases to compare with new specimens on the same patient when needed (I have to do this often in my practice). But it means that I could go and search for any rare tumor, pull it out, look at it and see all patient identifiers, and as long as I was doing that for quality control or my own education, it would be totally OK. Even the new proposed regulations would not prevent this.

“But as soon as I want to take that tissue and compare it to other similar cases and learn something from it to write up and publish and share with the medical community, then it becomes ‘research’ and is subject to all sorts of rules. I understand why all of these rules exist, but sometimes they strike me as not only unnecessary but even as a bit ridiculous when it comes to the type of research we usually do in pathology.

“As a pathologist, all of the tissue is at my fingertips and can be accessed and identified any day of the week, and yet privacy breach isn't a concern when I go to work every day because I am a physician and I respect and hold dear the rights of my patients. I would never voluntarily compromise their privacy. But if I pull 20 cases (oftentimes cases that I originally saw and diagnosed!) to look at for a research project, then I have to jump through hoops to protect privacy and meet other regulatory requirements.

“I do jump through the hoops since that is the rule and I want to stay out of trouble, but in pathology we get painted with the same brush that is used for other specialties even though it isn't really very pertinent or appropriate for the work and research that we usually do. I understand why this happens. We are a unique field that works behind the scenes. Most doctors don't fully understand the work we do. How could I expect lawmakers and IRBs and administrators to have a firm grasp on it?”

Dr. Andrew Rosenberg

If the changes are adopted, there has to be a push to obtain informed consent and have this information easily available to research through electronic medical records, said Andrew E. Rosenberg, M.D., director of Bone & Soft Tissue Pathology at the University of Miami. “Maybe this information can be organized in tumor registries that many hospitals have.”

Dr. Gardner was less hopeful. “It is yet another form for patients to read and sign and for administration people to track and file, so it adds complexity and burden to the already vastly overburdened system. How will the pathologist know if the patient had signed this form or not? So many electronic medical records are difficult to use and finding documents can be very challenging, especially in a patient with a complex disease (like sarcoma, for example!) requiring multiple hospital stays and visits with numerous associated forms each time.

“Just figuring out if the patient signed a form or not may take a lot of extra time and effort. This roadblock to research would either result in pathologists wasting valuable time finding paperwork or it would just push even more pathologists away from doing research at all because of all the regulatory headaches.

“Even with a 3-year phase-in, many hospitals and clinics, particularly smaller ones, may not implement this form (or not implement it routinely) meaning that none of their tissue could be used for research without first tracking down the patient to get permission. In my research studies of rare sarcomas and soft-tissue tumors, many of the cases originated from small laboratories or hospitals and were then sent in to us for expert consultation.

“Many research studies of rare tumors conducted by pathology experts will deal largely with consultation material like this. So even if the expert works at a major academic medical center that is very good about getting permission forms signed on its own patients, the vast majority of the cases will be from outside of the system where it will be hit or miss whether permission has been obtained or not.

“I have personally spent HUNDREDS of hours on the phone trying to track down patients with rare diseases to obtain follow up information for research studies; it is often impossible to locate patients years after treatment as they may have moved or transferred to another physician for care.

“It will become more complicated to use tissue for research that came after the new rule change. Thus I suspect many pathologists will just conduct research on older tissue since it will be grandfathered and avoid the complexity of the new regulations. We need research on new material and new types of disease, and this rule may limit that.”