Monday, January 25, 2016

'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.

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