A rare opportunity

I presented the Alliance's poster at AACR.

By Suzie Siegel
Someday all cancers will be rare.

So says Rick Pazdur, MD, director of the FDA's Oncology Center of Excellence. As physicians and scientists learn more about genetics, they are breaking down cancers into smaller and smaller categories that may respond to specific drugs.

Dr. Pazdur spoke this spring to a group of advocates who won scholarships to attend the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C. I was the only sarcoma advocate in the Scientist↔Survivor Program, but that’s not surprising, considering sarcoma represents only 1 percent of adult cancer cases.

Carcinomas – what most people call cancer – are named for where they occur in the body, such as breast cancer or colon cancer. Sarcomas are named for the cells in which they are thought to come from. But sarcoma subtypes are now being divided still further.

“Histological classifications are now supplemented by molecular subclassifications, which strongly influence prognosis and guide treatment decisions. More than ever, sarcomas are regarded as a complex and fragmented collection of uncommon entities, altogether rare and often extremely rare,” Jean-Yves Blay, MD, PhD, director of the Centre Léon Bérard in Lyon, France, wrote in Future Medicine. An example is liposarcoma, which arises in fat cells. It has been separated into well-differentiated, dedifferentiated, myxoid and pleomorphic liposarcoma.

Results of the largest study of sarcoma genetics were published last year, with more data coming from the Garvan Institute in Sydney, Australia. It leads the International Sarcoma Kindred Study, which is looking at the genetics of more than 1,000 people.

We also await more results from The Cancer Genome Atlas, a project of the National Cancer Institute in Bethesda, Md. Anna Barker, PhD, chair of the AACR survivor program, helped conceive and develop TCGA when she was deputy director of the NCI.  She is now co-director of Complex Adaptive Systems and director of the National Biomarker Development Alliance at Arizona State University in Tempe.

At the recent American Society of Clinical Oncology (ASCO) meeting in Chicago, a study was presented on an experimental drug named larotrectinib that targets TRK gene fusions. Some sarcoma patients should benefit.
 
The clinical trial was done basket-style, enrolling patients with different types of cancer. Getting enough sarcoma patients for meaningful research takes time; I think we benefit from basket studies that include people with other cancers. In a sense, many clinical trials in sarcoma have been basket studies because they enrolled people with different sarcoma subtypes.

Dr. Rick Pazdur

Companies need clinical trials to get their drugs approved. But Dr. Pazdur believes: “Clinical trials are here to serve the patient. Patients are not here to serve clinical trials.”

The FDA used to require companies prove that their drugs would help patients live longer. This can be hard to measure, in part because some patients have very advanced cancer by the time they go on a clinical trial. The FDA now approves some drugs if patients can go longer without their cancer progressing than they could on a standard drug. This change allowed trabectedin (Yondelis) to be approved for liposarcoma and leiomyosarcoma, for example.

I hope the FDA will use similar criteria to approve aldoxorubicin, which I wrote about in 2014.

Dr. Pazdur wants to expand access to clinical trials for patients who might not qualify because of how advanced their cancer is. He has suggested other innovations here and here. But he said he can do only so much because drug companies pay for almost all clinical trials. They control eligibility requirements, except where safety and a few other issues are concerned.

His desire to expand access stops at the “Right to Try” laws, which allow people with terminal illnesses to take unapproved drugs outside of trials. He said these laws directly contradict the Food, Drug and Cosmetic Act, which requires the FDA to oversee drug safety.

Trials are much more likely to be done in North America, Europe and Asia than in South America or Africa. That needs to be rectified, Dr. Pazdur said, to see if different populations respond differently to new drugs.

The AACR meeting drew 22,850 people from 60 countries, said CEO Margaret Foti, MD, PhD. She has spent 35 years with the organization and sees a much greater emphasis on cancer prevention.

Sarcoma researchers have been active in the AACR since its founding 110 years ago. The founders included Dr. William Coley, considered the father of immunotherapy, and Dr. James Ewing,  AACR’s first president. Dr. Ewing discovered the bone sarcoma that bears his name.  

George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston, is on AACR’s current board. He decries cuts in federal funding for cancer research. “I do not believe for one second this is what the public wants.” 

Dr. Drew Pardoll

Recent gains in immunotherapy show the importance of investing in science even when the payoff isn’t immediate, said Drew Pardoll, MD, PhD, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University in Baltimore. He has been working in the field more than 30 years.

“Cancer genetics has married immunotherapy,” said Dr. Pardoll, discussing how pembrolizumab (Keytruda) works in people with DNA mismatch-repair deficiency (MMR), which causes microsatellite instability (MSI).

After approving Keytruda last month for this genetic defect, the FDA noted: “This is the first time the agency has approved a cancer treatment based on a common biomarker.”

Stefanie Joho

The evidence for supporting immunotherapy stood by Dr. Pardoll’s side: Stefanie Joho of Philadelphia, whose colon cancer disappeared after she joined a clinical trial for Keytruda. She recalled when she was inoperable: “The doctors say there’s nothing they can do. There’s no more hope. I’m ready to give up. I basically feel dead.”

Then her sister found the study at Hopkins. “The public has a misconception of clinical trials. I did, too. I was under the impression they were the last resort. I’d just be a guinea pig. But right now, you could be getting the most precise treatment for your specific kind of cancer.

“How do you go through an experience like this and not want to advocate, not just for other patients, but for cancer research?”

Suzie Siegel, a 15-year survivor of leiomyosarcoma, is a former board member of the Sarcoma Alliance. 

Hot topics in genomics and immunotherapy

By Suzie Siegel

Sitting outside a sarcoma conference hall, she could have been anyone. She was down-to-earth and answered questions with the patience of a teacher.

Elaine Mardis, PhD

But she turned out to be Elaine Mardis, PhD, a renowned scientist and board member of the American Association for Cancer Research. It was 2015, and she had helped organize the AACR’s “Basic Science of Sarcomas,” its first conference on the subject. Last year, she became co-director of the Institute for Genomics Medicine at Nationwide Children’s Hospital in Columbus, Ohio.

The human genome is a genetic blueprint – a complete set of DNA – to tell our bodies how to develop. Physicians and scientists study the genome in hopes of finding the genetic changes that cause cancer or allow it to grow out of control. The goal is precision medicine (also called targeted therapy), in which treatments are matched to specific gene mutations. This differs from traditional chemotherapy with cytotoxic drugs that kill some healthy cells along with the cancer.

A famous example of precision medicine is the use of imatinib (Gleevec) for gastrointestinal stromal tumors (GISTs) that express the protein KIT.

A decade ago, I wrote about the hype surrounding precision medicine. It had not – and still has not – paid off as much or as soon as many predicted. Nevertheless, I still have great hope for it, and I was surprised recently to encounter doctors who thought it had little future.

“I don't think there are many people saying there is little future for precision medicine, really, who have any position of expertise/experience in the field,” Dr. Mardis said. “Fact is, we now are seeing reports emerge in the peer-reviewed literature that are indicating strong clinical benefit for these [genetic] tests in cancer patients. These large-number trials are establishing strong evidence that testing patients to predict their best drug/treatment options is worthwhile and should be pursued.”

For example, Nationwide Children’s is planning a trial using exome-sequencing to find targetable gene mutations in pediatric patients with treatment-refractory sarcoma, she said. This testing looks at the DNA that encodes proteins.

“The aim is to identify kids that might benefit from a targeted therapy or to detect those who might benefit from checkpoint-blockade therapy.” Checkpoint blockade is one tool of immunotherapy.

For those who say immunotherapy isn’t worth it, Dr. Mardis responds: “Ask someone who was at death's door and now is living a normal life. There are plenty [of immunotherapy drugs] to choose from already, and it's early days.

“I think the challenge in immunotherapy is that we need to better be able to define which patients will respond to it, and to be able to clinically monitor those likely to have adverse responses so they can be properly cared for during the difficult clinical period, thereby experiencing the long-term benefit of these therapies.

“The other open question in checkpoint blockade is the specifics around dosing, because it is quite clear we have patients who receive only one or a few rounds of therapy and have a durable response.”

Another hotly debated issue in precision medicine is the use of randomized controlled trials. In a recent panel discussion, one oncologist “indicated the trials for targeted therapies are not appropriately designed because patients with mutations in druggable target genes weren't being randomized to a placebo or standard-of-care arm.”

This may be appropriate for a phase IIa trial involving only a few patients, Dr. Mardis said. Once a targeted therapy has shown promise, however, patients don’t want to sign up for a phase IIb trial in which they may get a placebo or the older standard of care, she said.

“The ethics of putting a patient onto SOC [standard-of-care treatment] when they are likely to respond based on phase IIa results is questionable, in my mind. Some trials have solved this by using a ‘cross-over’ potential for patients who clearly are having no response, so they can get the drug being trialed.

“Medicine is an evidence-based practice, and all doctors do the best they can for their patients, but since this is such a new area, there are likely to be disagreements. The fundamental differences in targeted versus cytotoxic chemotherapies also evoke new ideas about clinical-trial design that are controversial.”

I often hear people complain that the FDA approves expensive new drugs that give cancer patients only a few more months of life than the older drugs do. These complaints are misleading, Dr. Mardis said, because those few months are an average of everyone’s response on the clinical trial. Some people may live for years while others get no benefit.

“Furthermore, there are myriad examples of patients who achieved a short benefit that bought them sufficient time for a better therapy to come along,” she said. “I was just speaking to the mother of one such patient with low-grade glioma. When we identified her daughter's driver BRAF mutation (a three nucleotide insertion that added an amino acid after position 600) in 2011, nobody had ever enrolled on a BRAF inhibitor trial (that we could identify) with that type of insertion and so her likelihood of response was unknown.

“As an alternative, she got a MEK inhibitor but didn't have a response after six months, which was long enough for someone to have seen a similar BRAF mutation who did respond to RAF inhibition. She then switched to a second-generation RAF inhibitor and has been responding now for over a year.”

“From Basic Science to Clinical Translation” will be the AACR’s next conference on sarcoma May 16-19 in Philadelphia. Its general meeting will be April 1-5 in Washington, D.C. I'm grateful for winning a scholarship to attend, as part of its Scientist↔Survivor Program. Sarcoma Alliance board member Dave Murphy participated in this program in 2004 and 2005. He returned in 2014 as an advocate mentor.

'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.