Журнал онкологических трансляционных исследований

The treatment of metastatic Non-small Cell Lung Cancer (mNSCLC) has evolved from traditional doublet chemotherapy to a model for precision medicine. Over the past fifteen years, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations as key players in the pathogenesis of mNSCLC has transformed the care of patients with mNSCLC. EGFR Tyrosine Kinase Inhibitors (TKIs) have prolonged both progression free survival and overall survival in patients who harbor EGFR mutations. Most recently, the third generation EGFR TKI osimertinib has shown superior progression free survival compared to earlier TKIs. Osimertinib has also shown excellent penetration into the CNS, less CNS tumor progression, and even leptomeningeal disease response. The efficacy of EGFR TKIs in the CNS may allow clinicians to avoid or defer radiation therapy for CNS disease in select mNSCLC patients with EGFR mutations. The advent of circulating tumor DNA (ctDNA) has shown excellent diagnostic concordance with tumor biopsy in detecting EGFR mutations. While not the most sensitive tests, ctDNA is highly specific in uncovering EGFR mutations. In the future, ctDNA will likely avoid many unnecessary tissue biopsies in suspected lung cancer. As a marker of disease burden, ctDNA load will also play a key complementary role in determining response to therapy, disease resistance, and associated prognosis in EGFR mutated mNSCLC. In light of these remarkable advances, testing for mutations in EGFR, in addition to mutations in ALK, ROS-1, BRAF and PD-L1, is now more than ever the standard of care for mNSCLC, and critical to precision medicine.

Temozolomide (TMZ), thymoquinone (TMQ), epigallocatechin gallate (EPIGAL) and staurosporine (STAURO) were used as apoptotic inducing agents acting upon the U87-MG (ATCC, HTB15), LN18 (ATCC, CRL2610) and U118-MG (ATCC, HTB14) glioblastoma multiforme (GBM) cell lines. TMZ is the current drug of choice for primary treatment and adjuvant therapy for recurrent GBM. TMQ and EPIGAL are naturopathic agents, while STAURO is a well-studied apoptotic-inducing agent. The degree and time course of apoptosis were measured by flow cytometry techniques capable of detecting changes in mitochondrial function using the fluorescent dye MitoTracker Deep Red. Phosphatidylserine exposure and plasma membrane permeability were detected simultaneously using violet fluorescent reactive dye (VFRD) in combination with AnnexinV-488. The apoptotic effectiveness of the inducing agents TMZ, TMQ, EPIGAL and STAURO were compared with their ability to inhibit invasiveness and degrade Class I major histocompatibility complex (MHC) determinants. Invasiveness was measured in vitro by the 3D matrigel spheroid invasion assay. The density of the class 1 MHC determinants was measured by flow cytometry. Although TMZ is widely used for the chemotherapeutic treatment of GBM, it was determined that the time course for TMZ induced apoptosis was slower than those of TMQ, EPIGAL and STAURO. Unexpectedly, TMZ was ineffective in its ability to inhibit in vitro invasiveness and did not degrade the class I MHC determinants as effectively as the other apoptotic inducing agents. The findings raise the question of whether in vitro assays of apoptosis and invasiveness are the best measures of the effectiveness of chemotherapeutic agents for the primary treatment and adjuvant therapy of recurrent GBM. The findings also point to the in vivo complexity of the efficacy of chemotherapeutic agents whereby preserving the components of natural and acquired immune mechanisms may be more important than the rapid apoptotic effects of the chemotherapeutic agent.