Absence of Biomarker-Driven Treatment Options in Small Cell Lung Cancer, and Selected Preclinical Candidates for Next Generation Combination Therapies

Abstract

Lung cancer is the second most common cancer in the United States, and small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. In SCLC, more than other malignancies, the standard of care is based on clinical demonstration of efficacy, and less on a mechanistic understanding of why certain treatments work better than others. This is in large part due to the virulence of the disease, and lack of clinically or biologically relevant biomarkers beyond routine histopathology. While first line therapies work in the majority of patients with extensive stage disease, development of resistance is nearly universal. Although neuroendocrine features, Rb and p53 mutations are common, the current lack of actionable biomarkers has made it difficult to develop more effective treatments. Some progress has been made with the application of immune checkpoint inhibitors. There are new agents, such as lurbinectedin, that have completed late-phase clinical testing while other agents are still in the pre-clinical phase. ONC201/TIC10 is an imipridone with strong in vivo and in vitro antitumor properties and activity against neuroendocrine tumors in phase 1 clinical testing. ONC201 activates the cellular integrated stress response and induces the TRAIL pro-apoptotic pathway. Combination treatment of lurbinectedin with ONC201 are currently being investigated in preclinical studies that may facilitate translation into clinical trials for SCLC patients.

One sample fits all: a microfluidic-assisted methodology for label-free isolation of CTCs with downstream methylation analysis of cfDNA in lung cancer

“…Lack of comprehensive knowl-edge on markers that may aid in early diagnosis, disease monitoring and identification of therapeutic targets also contribute to the high mortality rates. [4][5][6] Nevertheless, significant progress has been made recently, with the employment of minimally invasive techniques for cancer screening and monitoring, based on blood-derived cancer biomarkers, which may significantly impact on LC patient' outcome and enable Precision Medicine. Indeed, the analysis of tumour biomarkers present in liquid biopsies (blood) and in bodily fluids (urine, pleural and cerebrospinal fluid) can provide real-time assessment of the disease and its molecular and genetic landscape.…”

“…Lack of comprehensive knowledge on markers that may aid in early diagnosis, disease monitoring and identification of therapeutic targets also contribute to the high mortality rates. 4–6…”

The efficacy and safety of anlotinib for subsequent line treatment of small cell lung cancer: a systematic review and meta-analysis

“…Lung cancer is one of the most malignant tumors with high morbidity and mortality worldwide. 1 Small-cell lung cancer (SCLC) accounts for about 15% of all lung cancers, 2 and most patients are diagnosed with extensive-stage disease due to a lack of specific symptoms and signs during the early stages. 3 For decades, a platinum-containing dual-drug combination chemotherapy regimen has been the first-line standard treatment option for SCLC.…”

A microfluidics-assisted methodology for label-free isolation of CTCs with downstream methylation analysis of cfDNA in lung cancer

“…Lack of comprehensive knowledge on markers that may aid in early diagnosis, disease monitoring and identification of therapeutic targets also contribute to the high mortality rates. [4][5][6] Nevertheless, significant progress has been made recently, with the employment of minimally invasive techniques for cancer screening and monitoring, based on blood-derived cancer biomarkers, which may significantly impact on LC patient' outcome and enable Precision Medicine. Indeed, the analysis of tumour biomarkers present in liquid biopsies (blood) and in bodily fluids (urine, pleural and cerebrospinal fluid) can provide real-time assessment of the disease and its molecular and genetic landscape.…”

“…Lack of comprehensive knowledge on markers that may aid in early diagnosis, disease monitoring and identification of therapeutic targets also contribute to the high mortality rates. 4–6…”