Abstract
Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific “driver” mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, “elephant in the room”, is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and ‘tame the beast of resistance’, thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to “prime” tumors and reverse resistance.
Highlights
The success stories of childhood ALL, testicular cancer, and Hodgkins’ disease notwithstanding, malignancies that were once universally fatal, but are generally curable, the progress on other oncology fronts has been, at best, lamentably slow or, at worst, virtually nonexistent with the prospects for long-term survival generally measuring in months rather than years [1].Lung cancer, in particular, dominates as the leading cause of death among men and women in North America, an unenviable distinction that the three other most prevalent types of cancers, colon, breast, prostate, do not come close to sharing [2]
This article reviews the role of epigenetic dysregulation in non-small cell lung cancer (NSCLC), explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to “prime” tumors and reverse resistance
The authors identified a unique signature of activity in 25% of these refractory patients where response was deferred to the immediate line of post-study therapy, which is compatible with a priming effect on subsequent treatments [94]. These priming effects have been observed with RRx-001, a systemically non-toxic dual inhibitor of histone deacetylase inhibitors (HDACs) and DNA methyltransferases, where so far in a randomized Phase II trial with regorafenib 7/10 colorectal cancer (CRC) patients have been resensitized to previously failed irinotecan for 4 months or longer post-RRx-001 progression, which suggests that RRx001 epigenetically disrupts multiple cellular processes including chemoresistance, possibly through the derepression of tumor suppressor genes like p53 [95, 96]
Summary
The success stories of childhood ALL, testicular cancer, and Hodgkins’ disease notwithstanding, malignancies that were once universally fatal, but are generally curable, the progress on other oncology fronts has been, at best, lamentably slow or, at worst, virtually nonexistent with the prospects for long-term survival generally measuring in months rather than years [1].Lung cancer, in particular, dominates as the leading cause of death among men and women in North America, an unenviable distinction that the three other most prevalent types of cancers, colon, breast, prostate, do not come close to sharing [2]. Erlotinib was approved in 2004 for the treatment of patients with locally advanced or metastatic NSCLC after the failure of one or two prior chemotherapy regimens with a single agent response rate of 8.3 % and a median overall survival of 6.3 months [47].To date it remains the only approved third line therapy for NSCLC.
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