Worldwide, lung cancer is the most common cause of cancer-related deaths. Molecular targeted therapies and immunotherapies for non-small-cell lung cancer (NSCLC) have improved outcomes markedly over ...the past two decades. However, the vast majority of advanced NSCLCs become resistant to current treatments and eventually progress. In this Perspective, we discuss some of the recent breakthrough therapies developed for NSCLC, focusing on immunotherapies and targeted therapies. We highlight our current understanding of mechanisms of resistance and the importance of incorporating genomic analyses into clinical studies to decipher these further. We underscore the future role of neoadjuvant and maintenance combination therapy approaches to potentially cure early disease. A major challenge to successful development of rational combination therapies will be the application of robust predictive biomarkers for clear-cut patient stratification, and we provide our views on clinical research areas that could influence how NSCLC will be managed over the coming decade.
Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle ...checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.
Altered cell metabolism is inherently connected with pathological conditions including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's ...sarcoma (KS). KS tumour cells display features of lymphatic endothelial differentiation and in their vast majority are latently infected with KSHV, while a small number are lytically infected, producing virions. Latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, the metabolic properties of KSHV-infected cells closely resemble the metabolic hallmarks of cancer cells. However, how and why KSHV alters host cell metabolism remains poorly understood. Here, we investigated the effect of KSHV infection on the metabolic profile of primary dermal microvascular lymphatic endothelial cells (LEC) and the functional relevance of this effect. We found that the KSHV microRNAs within the oncogenic cluster collaborate to decrease mitochondria biogenesis and to induce aerobic glycolysis in infected cells. KSHV microRNAs expression decreases oxygen consumption, increase lactate secretion and glucose uptake, stabilize HIF1α and decreases mitochondria copy number. Importantly this metabolic shift is important for latency maintenance and provides a growth advantage. Mechanistically we show that KSHV alters host cell energy metabolism through microRNA-mediated down regulation of EGLN2 and HSPA9. Our data suggest that the KSHV microRNAs induce a metabolic transformation by concurrent regulation of two independent pathways; transcriptional reprograming via HIF1 activation and reduction of mitochondria biogenesis through down regulation of the mitochondrial import machinery. These findings implicate viral microRNAs in the regulation of the cellular metabolism and highlight new potential avenues to inhibit viral latency.
APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur ...at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV− head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV− HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for the generation of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Our findings implicate APOBEC activity as a key driver of PIK3CA mutagenesis and HPV-induced transformation.
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•APOBEC-mediated mutagenesis is increased in the HPV+ subset of head and neck cancer•APOBEC enzymes likely generate many of the driver mutations in HPV-associated cancers•APOBECs are implicated in generating the oncogenic E542K and E545K PIK3CA mutations
The APOBEC family of cytidine deaminases, which combat viral infection by hyperediting viral DNA, has recently been implicated in producing somatic mutations in human tumors. By analyzing mutation data from The Cancer Genome Atlas project, Henderson et al. provide evidence that this process plays a key role in tumor development by generating oncogenic hot spot mutations in the PIK3CA gene. This mechanism appears particularly prominent in tumors caused by the human papillomavirus, in which APOBEC activity accounts for a high fraction of the total mutational burden.
The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop titled “Next generation strategies for gene-targeted therapies of central nervous system (CNS) disorders” in ...September 2019 in Bethesda, MD, USA. The meeting brought together a multi-disciplinary group of experts in the field of CNS-directed gene-targeted therapy delivery from academia, industry, advocacy, and the government. The group was charged with identifying the key challenges and gaps in this evolving field, as well as suggesting potential solutions. The workshop was divided into four sessions: (1) control of level and location, (2) improving delivery and distribution, (3) enhancing models and manufacturing, and (4) impacting patients. Prior to the workshop, NINDS established working groups of key opinion leaders (KOLs) for each session. In pre-meeting teleconferences, KOLs were tasked with identifying the research gaps and key obstacles that delay and/or prevent gene-targeted therapies to move into the clinic. This approach allowed for the workshop to begin with problem-solving discussions and strategy development, as the key issues had been established. The overall purpose of the workshop was to consider knowledge gaps and potential strategies to inform the community around CNS gene-targeted therapies, including but not limited to researchers and funders.
The overall purpose of the workshop was to consider knowledge gaps and potential strategies to inform the community around CNS gene-targeted therapies, including but not limited to researchers and funders.
MicroRNAs are small, non-coding RNAs that negatively regulate gene expression. It has been proposed that microRNAs could function in the regulation of innate immunity, but this has not been ...demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity.
Summary Background Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We ...investigated whether erlotinib improves clinical outcome in these patients. Methods TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. Findings Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2–4·2, vs placebo, 3·6 months, 3·2–3·9; unadjusted hazard ratio HR 0·94, 95% CI 0·81–1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63–0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05–1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% 28 of 334 vs 1% four of 313, p=0·0001), as was high-grade rash (23% 79 of 334 vs 2% five of 313, p<0·0001); other adverse events were much the same between groups. Interpretation Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. Funding Cancer Research UK, Roche.
Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogramming of endothelial cells. In particular, KSHV-infected lymphatic endothelial cells (LECs) show an up-regulation of genes associated ...with blood vessel endothelial cells (BECs). Consequently, KSHV-infected tumor cells in Kaposi sarcoma are poorly differentiated endothelial cells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs) are short noncoding RNA molecules that act post-transcriptionally to negatively regulate gene expression. Here we validate expression of the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstrate that these miRNAs contribute to viral-induced reprogramming by silencing the cellular transcription factor MAF (musculoaponeurotic fibrosarcoma oncogene homolog). MAF is expressed in LECs but not in BECs. We identify a novel role for MAF as a transcriptional repressor, preventing expression of BEC-specific genes, thereby maintaining the differentiation status of LECs. These findings demonstrate that viral miRNAs could influence the differentiation status of infected cells, and thereby contribute to KSHV-induced oncogenesis.
Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis ...of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach.
Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings.
HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors.
These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.
Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of ...tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.
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