Summary: Researchers have identified a new pharmacological agent that could help to treat glioblastoma brain cancer.
Source: National Foundation for Cancer Research.
The National Foundation for Cancer Research (NFCR) today congratulated Dr. Web Cavenee and Dr. Paul B. Fisher on their discovery of a new pharmacological agent to treat glioblastoma multiforme (GBM), the deadliest brain cancer, which they have been developing together with NFCR support.
This new pharmacological agent could – with additional chemistry – lead to a new drug to prevent radiation-induced invasion of GBM cells. The researchers have tested their pharmacological agent in combination with radiation with profound survival benefits in pre-clinical models.
Paul B. Fisher, M.Ph., Ph.D., Director of the Virginia Commonwealth University’s (VCU) Institute of Molecular Medicine (VIMM), focuses on cancer genetics and Web Cavenee Ph.D., Director of the Ludwig Institute for Cancer Research at the University of California at San Diego focuses on GBM. An exciting breakthrough for the treatment of GBM, this is about collaboration between two scientists on opposite coasts and shows how NFCR research may lead to tangible therapies for multiple cancers.
NFCR has been funding Dr. Fisher’s research since 2008, and Dr. Cavenee’s research starting in 2002. “NFCR scientists are making headway in the fight against one of the most aggressive form of cancer, GBM, by working together on vital pre-clinical models,” said Franklin C. Salisbury, Jr., NFCR CEO. “For years, discoveries from NFCR-funded research have led to better treatments today – and this latest discovery by two incredibly talented scientists gives us proof there will be improved therapies for GBM and multiple cancers in the foreseeable future.”
Funding: Funding provided by National Foundation for Cancer Research, Army Department of Defense.
Source: Allyson Kehoe – National Foundation for Cancer Research
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin” by Timothy P. Kegelman, Bainan Wu, Swadesh K. Das, Sarmistha Talukdar, Jason M. Beckta, Bin Hu, Luni Emdad, Kristoffer Valerie, Devanand Sarkar, Frank B. Furnari, Webster K. Cavenee, Jun Wei, Angela Purves, Surya K. De, Maurizio Pellecchia, and Paul B. Fisher in PNAS. Published online December 23 2016 doi:10.1073/pnas.1616100114
Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin
Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.
“Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin” by Timothy P. Kegelman, Bainan Wu, Swadesh K. Das, Sarmistha Talukdar, Jason M. Beckta, Bin Hu, Luni Emdad, Kristoffer Valerie, Devanand Sarkar, Frank B. Furnari, Webster K. Cavenee, Jun Wei, Angela Purves, Surya K. De, Maurizio Pellecchia, and Paul B. Fisher in PNAS. Published online December 23 2016 doi:10.1073/pnas.1616100114