Abstract
Adult diffuse glioma, particularly glioblastoma (GBM), is a devastating tumor of the central nervous system. The existential threat of this disease requires on-going treatment to counteract tumor progression. The present outcome is discouraging as most patients will succumb to this disease. The low cure rate is consistent with the failure of first-line therapy, radiation and temozolomide (TMZ). Even with their therapeutic mechanism of action to incur lethal DNA lesions, tumor growth remains undeterred. Delivering additional treatments only delays the inescapable development of therapeutic tolerance and disease recurrence. The urgency of establishing lifelong tumor control needs to be re-examined with a greater focus on eliminating resistance. Early genomic and transcriptome studies suggest each tumor subtype possesses a unique molecular network to safeguard genome integrity. Subsequent seminal work on post-therapy tumor progression sheds light on the involvement of DNA repair as the causative contributor for hypermutation and therapeutic failure. In this review, we will provide an overview of known molecular factors that influence the engagement of different DNA repair pathways, including targetable vulnerabilities, which can be exploited for clinical benefit with the use of specific inhibitors.
Highlights
Therapeutic resistance is a known phenomenon that continues to be a formidable foe in the search for a curative treatment
Retrospective assessment of pair-matched de novo and post-treated malignant tumors have uncovered that the genetic evolutionary trajectories are a prelude to clonal replacement; therapies ablate vulnerable cancer cells to positively select for resistant clones to proliferate
Postulation is that malignant is dependent on oncogenes to mount a strongto mount reasonable postulationprogression is that malignant progression is dependent on oncogenes proliferative index for tumor growth, which has an indirect consequence in mutational a strong proliferative index for tumor growth, which has an indirect consequence in muburden
Summary
Therapeutic resistance is a known phenomenon that continues to be a formidable foe in the search for a curative treatment. The characteristics of GNS cells are frequently observed in non-responsive patients who have received the Stupp protocol, a first-line treatment regime that utilizes both radiotherapy and TMZ to deliver fatal DNA double stand breaks (DSBs) [4,5] Such modalities are inadequate to eliminate tumor cells and it is not uncommon to find a residual cell population as a source of recurrence. Retrospective assessment of pair-matched de novo and post-treated malignant tumors have uncovered that the genetic evolutionary trajectories are a prelude to clonal replacement; therapies ablate vulnerable cancer cells to positively select for resistant clones to proliferate It is unlikely repeated radiation or TMZ treatment in recurring GBM will attain further progression of a freesurvival period. Modern radiotherapy techniques or DNA-damage inducing agents are inadequate to yield superior outcomes unless prohibition of specific DNA repair is carried out
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