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DNA Damage Response (DDR) signaling in tumor formation and therapeutic resistance of gliomas

Final Report Summary - GLIDD (DNA Damage Response (DDR) signaling in tumor formation and therapeutic resistance of gliomas)

The gliomas are a large group of brain cancers that include astrocytomas, oligodendrogliomas and oligoastrocytomas. Glioblastoma Multiforme (GBM), the highest grade of malignant astrocytomas (WHO grade IV), is the most common and lethal primary central nervous system (CNS) tumor in adults. Standard therapy for GBMs includes resection of the tumor mass, followed by concurrent radiotherapy and chemotherapy. Although the last decade highlighted enormous advances in treating other solid cancers, such as lung and breast, the median survival for GBM stayed nearly the same over the last 50 years, averaging 15 months. Nevertheless, the therapeutic strategy for gliomas has remained essentially unchanged for decades due to a limited understanding of the biology of the disease. Gaining insights into the pathways that determine this poor treatment response will be instrumental for the development of new therapeutic modalities for GBM patients. Recent findings suggest that the genetic alterations that characterize GBM genomes contribute also to the poor treatment response of this tumor type, by modulating the activity of the DNA damage checkpoints and the DNA repair machinery.
Preservation of genomic integrity is an essential process for cell homeostasis and defects in the DNA Damage Response (DDR), a complex network of proteins required for cell-cycle checkpoint and DNA repair, have been associated at different level with tumorigenesis. The DDR signalling is a very intricate pathway and many of its components can be altered in a given tumor patient, offerings both challenges and opportunities from a treatment prospective.
Using different genetic approaches, such as shRNA screening and transposon-mediated insertional mutagenesis in human haploid cells, Dr. Squatrito has discovered some of the key DDR mediators of chemotherapy sensitivity in GBM. Most importantly, they have identified a novel alkylating agent that has the ability to potentiate the activity of temozolomide, the chemotherapeutic agent used as first-line treatment in GBM, and to overcome its main mechanisms of resistance.
With their studies, they have the potential of identifying not only novel biomarkers of therapy response but most importantly novel target that could increase therapy sensitivity and therefore extend the survival of GBM patients. Being the GBM a tumor for which there haven’t been great advances in survival and present such a dismal prognosis I believe that they could quickly get to test these novel approaches for compassionate use.
The addition of temozolomide to the standard radiotherapy regimen, despite the modest extension of patient survival, has been shown to be a cost-effective treatment for newly diagnosed glioblastoma. Further enhancement of these therapies response will certainly result in an increased cost-effective treatment option associated with improved quality of life and survival benefits for GBM patients.