Lung Cancer Research and Treatment: Global Perspectives and Strategic Calls to Action.

BACKGROUND: Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions. MATERIALS AND METHODS: Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action. RESULTS: Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority. CONCLUSIONS: Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials.

Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.

INTRODUCTION: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors. MATERIALS AND METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B. RESULTS: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional. CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited. GOV IDENTIFIER: NCT03724890.

Androgen 5-alpha-reductase type 2 is highly expressed and active in rat spinal cord motor neurones.

Spinal cord motoneurones express high levels of androgen receptor. However, in responsive tissue, the effects of testosterone is often mediated by the more potent androgenic derivative 5-alpha-dihydrotestosterone (DHT). This compound is formed in androgen target cells by the enzyme 5-alpha-reductase. Two isoforms of the 5-alpha-reductase, with limited degree of homology, have been cloned, type 1 and type 2. The low affinity-constitutive type 1 isoenzyme is widely distributed in the body; the high affinity-androgen regulated 5-alpha-reductase type 2 is confined to androgen-dependent structures and shows a peculiar pH optimum at acidic values. We have previously shown that high levels of 5-alpha-reductase activity are detectable in rat spinal cord. Here, using reverse transcriptase-polymerase chain reaction, we show that both isoforms are expressed in the whole spinal cord of the rat. The enzymatic pH optimum measured in immortalized spinal cord motoneurones (NSC34) is typical of the type 2 isoenzyme. Using in situ hybridization technique, we found that 5-alpha-reductase type 2 is confined to the motoneuronal cells of the anterior horns of the rat spinal cord, the cells that also are known to express high levels of androgen receptor. Because of the close association of androgen receptor and 5-alpha alpha-reductase type 2, motoneuronal cells should be considered as target cells for androgens.

Androgen-induced neurite outgrowth is mediated by neuritin in motor neurones.

In the brain, the spinal cord motor neurones express the highest levels of the androgen receptor (AR). Experimental data have suggested that neurite outgrowth in these neurones may be regulated by testosterone or its derivative 5alpha-dihydrotestosterone (DHT), formed by the 5alpha-reductase type 2 enzyme. In this study we have produced and characterized a model of immortalized motor neuronal cells expressing the mouse AR (mAR) [neuroblastoma-spinal cord (NSC) 34/mAR] and analysed the role of androgens in motor neurones. Androgens either activated or repressed several genes; one has been identified as the mouse neuritin, a protein responsible for neurite elongation. Real-time PCR analysis has shown that the neuritin gene is expressed in the basal condition in immortalized motor neurones and is selectively up-regulated by androgens in NSC34/mAR cells; the DHT effect is counteracted by the anti-androgen Casodex. Moreover, DHT induced neurite outgrowth in NSC34/mAR, while testosterone was less effective and its action was counteracted by the 5alpha-reductase type 2 enzyme inhibitor finasteride. Finally, the androgenic effect on neurite outgrowth was abolished by silencing neuritin with siRNA. Therefore, the trophic effects of androgens in motor neurones may be explained by the androgenic regulation of neuritin, a protein linked to neurone development, elongation and regeneration.