Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. ...Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%-30% of treated patients respond and the ability to predict ...clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.
We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (
= 303 unique patients) using a uniform computational approach.
Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (
< 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (
= 105).
Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.
The microbiome is increasingly recognized for its role in multiple aspects of cancer development and treatment, specifically in response to checkpoint inhibitors. While checkpoint inhibitors have ...revolutionized cancer treatment by producing durable anti-tumor responses, only a minority of patients respond to the available immunotherapy drugs and accurate, sensitive and specific microbiome predictors of response to treatment remain elusive. Additionally, the specific mechanisms linking the microbiome and host immunological responses remain unclear. In this review, we examine the evidence for the gut microbiome's association with anti-tumor responses to checkpoint inhibitors in the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma. Furthermore, we discuss the current evidence available from murine models seeking to explain the immunological mechanisms that may drive this process. While this work is promising in defining the impact of gut microbiota in cancer treatment, many unanswered questions indicate the need for additional human and experimental studies.
Small-cell lung cancer (SCLC) is aggressive and confers poor prognosis. Although SCLC shows more response to chemotherapy than other types of lung cancer, it is difficult to cure because of its ...frequent recurrence. New drugs and molecular targets need to be identified.
We investigated the effect of nelfinavir, an HIV protease inhibitor, on SCLC cells and in preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models.
Nelfinavir inhibited SCLC cell proliferation and induced cell death in vitro, which was caused by induction of the unfolded protein response (UPR), inhibition of mammalian/mechanistic target of rapamycin (mTOR) activation, and reduction in the expression of SCLC-related molecules such as achaete-scute homolog 1 (ASCL1). In vivo, nelfinavir inhibited the growth of SCLC PDX tumors, which correlated with the induction of UPR and reduced expression of ASCL1.
Nelfinavir is highly effective in SCLC in vitro and in vivo, suggesting possible incorporation of nelfinavir into clinical trials for patients with SCLC.
Nelfinavir is a human immunodeficiency virus protease inhibitor that is currently being repositioned as an anticancer drug. Chloroquine, an anti-malarial lysosomotropic drug, inhibits autophagy. It ...has been reported that the combination of nelfinavir and chloroquine significantly enhances endoplasmic reticulum (ER) stress and induces selective cell death in multiple cell line models (in vitro).
We assessed the effects of the combination of these drugs on human NSCLC cell lines in vitro using cell proliferation assay and performed preclinical treatment studies using cell line-derived xenograft mouse models in vivo.
In vitro, this combination enhanced inhibition of NSCLC cell proliferation with increased proteotoxicity, including ER stress, and apoptosis. In vivo, the growth of human NSCLC xenograft tumors was inhibited, which correlated with increased apoptosis and induction of ER stress as well as NSCLC growth in vitro.
Our findings suggest that the induction of proteotoxicity provides a promising new target for developing anticancer drugs.
The PI3K/Akt/mTOR pathway is aberrantly active in most human cancers and contributes to cell growth, proliferation, and survival. Akt is a nodal regulator of cellular survival pathways and an ...attractive target in cancer therapy. Many inhibitors of Akt are being developed. Perifosine is an oral Akt inhibitor currently being tested in phase 2 clinical trials. Unlike most kinase inhibitors, which target the adenosine triphosphate-binding region, perifosine targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Single-agent activity with perifosine has been observed in sarcoma and Waldenström macroglobulinemia patients. However, the disappointing response rates of common solid tumors to perifosine as a single agent have diminished expectations and prompted further investigation into its mechanism of action. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. In this article, we review the clinical history of perifosine and discuss its many biologic activities.
The influence of anthropometric characteristics on colorectal neoplasia biology is unclear. We conducted a systematic review and meta-analysis to determine if adult-attained height is independently ...associated with the risk of colorectal cancer or adenoma.
We searched MEDLINE, EMBASE, the Cochrane Library, and Web of Science from inception to August 2020 for studies on the association between adult-attained height and colorectal cancer or adenoma. The original data from the Johns Hopkins (Baltimore, MD) Colon Biofilm study was also included. The overall HR/OR of colorectal cancer/adenoma with increased height was estimated using random-effects meta-analysis.
We included 47 observational studies involving 280,644 colorectal cancer and 14,139 colorectal adenoma cases. Thirty-three studies reported data for colorectal cancer incidence per 10-cm increase in height; 19 yielded an HR of 1.14 95% confidence interval (CI), 1.11-1.17; P < 0.001), and 14 engendered an OR of 1.09 (95% CI, 1.05-1.13; P < 0.001). Twenty-six studies compared colorectal cancer incidence between individuals within the highest versus the lowest height percentile; 19 indicated an HR of 1.24 (95% CI, 1.19-1.30; P < 0.001), and seven resulting in an OR of 1.07 (95% CI, 0.92-1.25; P = 0.39). Four studies reported data for assessing colorectal adenoma incidence per 10-cm increase in height, showing an overall OR of 1.06 (95% CI, 1.00-1.12; P = 0.03).
Greater adult attained height is associated with an increased risk of colorectal cancer and adenoma.
Height should be considered as a risk factor for colorectal cancer screening.
The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated ...with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents.
HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non-small cell lung carcinoma (NSCLC) xenografts with biomarker assessment.
Three of six HIV protease inhibitors, nelfinavir, ritonavir, and saquinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 micromol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but nelfinavir caused the greatest inhibition of endogenous and growth factor-induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis.
Nelfinavir is a lead HIV protease inhibitor with pleiotropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, nelfinavir is a Food and Drug Administration-approved drug that could be repositioned as a cancer therapeutic.
T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic ...transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ‑secretase. γ‑secretase inhibitors (GSIs) are a NOTCH‑targeted therapy for T‑ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ‑secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH‑associated T‑ALL. The present study assessed the efficacy of nelfinavir against T‑ALL cells and investigated mechanisms of action
and in preclinical treatment studies using a
transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ‑secretase activity as well as the NOTCH1 pathway, thus suppressing T‑ALL cell viability. Additionally, microarray analysis of nelfinavir‑treated T‑ALL cells showed that nelfinavir upregulated mRNA levels of
(glutathione‑specific γ‑glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (
; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T‑ALL cells. Moreover, nelfinavir suppressed
mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating
mRNA expression, upregulating
and suppressing γ‑secretase via presenilin 1 inhibition and the mTOR pathway by upregulating
via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an
transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.
The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the ...identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery.
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