Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR‐driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single‐cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell‐mediated immune responses and protects mice against EGFRL858R mutation‐driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic‐ and granulocytic‐myeloid‐derived suppressor cells, regulatory T cells, and pro‐tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory‐like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR‐driven lung tumorigenesis and promotes an adaptive T cell‐mediated tumor‐specific immune response that enhances the efficacy of EVax.
Colorectal Cancer (CRC) is a major public health issue world-wide with an estimated 700,000 deaths annually. Adults 50 to 69 years of age considered high-risk for CRC can take low-dose Aspirin daily for at least 10 years to reduce their risk for CRC, according to a set of recommendations from the US Preventive Services Task Force. Naproxen is a highly efficacious CRC chemopreventive agent in animal models. Continuous/chronic usage of both drugs is limited by GI toxicity and unwanted side effects. Thus, the rationale to establish intermittent dosing regimens of Naproxen and Aspirin may provide efficacy without GI toxicity. Male F344 rats were used to establish Naproxen and Aspirin pharmacodynamic efficacy and dose-response effects. Rat (36 animals/group) colon cancers were induced by two weekly doses of azoxymethane (AOM). At the adenoma stage, rats were fed diets containing Naproxen (200 and 400 ppm) or Aspirin (700, and 1,400 ppm) either continuously, 1 week on/1 week off, or 3 weeks on/3 weeks off, or Aspirin (2,800 ppm) 3 weeks on/3 weeks off. All rats were euthanized 48 weeks after AOM treatment and assessed for efficacy, dose-response effects, and biomarkers in tumor tissues. Dietary administration of Naproxen and Aspirin did not show any overt-toxicities. Administration of 200 and 400 ppm of Naproxen inhibited colon adenocarcinoma multiplicity by 54.5% and 70.5% (p<0.0001) (continuous treatment); 53.3% and 68.4% (p<0.0001) (1 week on/1 week off); and 22.5% (p<0.03) and 61.5% (p<0.0001) (3 weeks on/3 weeks off), respectively. Importantly, inhibition of invasive colon carcinoma was reduced by 53% (p<0.0009) - >88% (p<0.0001) with different treatment regimens of Naproxen. With regard to colon adenocarcinoma multiplicity, Aspirin showed significant inhibitory effect with different treatment regimens with clear dose-response effects. Total adenocarcinomas (both invasive and non-invasive) multiplicities were suppressed by 41% (P<0.003) - 72% (p<0.0001). Particularly, Aspirin showed suppression of invasive colon adenocarcinomas by >67% (p<0.0001) - >91% (p<0.0001) with different treatment regimens. Based on the biomarkers of proliferation and apoptosis, both agents showed significant modulation of proliferative (PCNA, p21) and apoptotic markers (p53, Casp3) in colonic tumors. Transcriptomic data revealed that proinflammatory cytokines, particularly interleukins and metalloproteases, were significantly reduced in tumors of rats exposed to Aspirin and Naproxen. Overall, our results suggest that intermittent dosing with Naproxen or Aspirin demonstrated significant dose-response efficacy on the progression of adenomas to adenocarcinomas, particularly invasive carcinomas. {This work was supported by NCI-N01-CN-250026} Citation Format: Altaf Mohammed, Naveena B. Janakiram, Venkateshwar Madka, Yuting Zhang, Anil Singh, Laura Biddick, Qian Li, Stan Lightfoot, Vernon E. Steele, Ronald Lubet, Mark S. Miller, Chen S. Suen, Shizuko Sei, Chinthalapally V. Rao. Intermittent dosing regimens of naproxen and aspirin inhibit azoxymethane-induced rat colon adenoma progression to adenocarcinoma and carcinoma invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4983.
The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.Abstract Figure
Background: The National Cancer Institute (NCI) PREVENT Cancer Program (PREVENT) is a peer-reviewed R&D pipeline with the core emphasis on preclinical development and clinical translation of novel cancer preventive interventions. One of the latest PREVENT-supported projects include cGMP production and IND enabling studies of a broad spectrum experimental human papillomavirus (HPV) vaccine- HPV16 RG1-VLP. This monovalent chimeric virus-like particle (VLP) displays 360 copies of the highly conserved epitope RG1 (aa 17-36 of minor capsid protein HPV16 L2) in the DE loop of HPV16L1 VLP backbone, and is capable of eliciting broadly neutralizing antibodies that target several clinically relevant HPV genotypes. RG-1 induced cross-neutralizing titers are typically lower than anti-L1 antibodies generated by currently licensed HPV vaccines. Hence, durability of protection has been cited as a cause of concern. Here, using engineering-run cGMP grade HPV16-RG1VLPs formulated with alhdyrogel®, the durability of protection 6 month post-vaccination of HPV16 RG1-VLPs against Gardasil-9®, a licensed HPV vaccine was evaluated using an established papillomavirus disease model. Methods: New Zealand white rabbits (n=15 per treatment group) were administered three intra-muscular vaccinations of HPV16-RG1 (80 µg), human doses of Gardasil-9®, or no vaccine (adjuvant only). Following vaccination, in vivo protection was assessed against 8 high-risk oncogenic HPVs utilizing methods from an established cottontail rabbit papillomavirus (CRPV) disease model. Within each treatment group, 5 rabbits were challenged two weeks post-final vaccination (at peak serum ELISA titer), while another 5 were challenged six months post-final vaccination to assess durability of protection. The remainder 5 rabbits will be challenged one year post final vaccination. Results: During the peak-titer period, rabbits vaccinated with monovalent HPV16-RG1VLP were protected from disease development, which was comparable to the protection afforded by Gardasil-9®. Six months after final vaccination, despite lower serum titers, HPV16-RG1VLP immunized rabbits were still protected from disease development with vaccine efficacy comparable to that of Gardasil-9®. And, in some instances, HPV16-RG1VLP vaccine demonstrated a superior cross-protection. Conclusions: Even as a monovalent formulation, HPV16 RG1 VLP vaccination was able to provide comparable protection against a number of high-risk oncogenic HPV types, including types not covered by Gardasil-9®, even after six months post-vaccination. As a monovalent VLP, HPV16 RG1 VLP holds promise as a broad-spectrum preventative vaccine candidate that could potentially provide broader protection at lower production costs. Studies evaluating protection one-year-post vaccination is currently in progress. Citation Format: Jiafen Hu, Karla Balogh, Ken Matsui, Huimin Tan, Pola Olczak, George Buchman, Brian Howard, Jonathan White, Michelle Kennedy, Shizuko Sei, Elizabeth Glaze, Sarah Brendle, Christina Schellenbacher, Reinhard Kirnbauer, Richard Roden, Robert Shoemaker, Neil Christensen, Joshua Weiyuan Wang. A cGMP-grade chimeric papillomavirus candidate vaccine (HPV16 RG1-VLP) confers long term cross-protection compared to a nonavalent hpv vaccine in a pre-clinical papillomavirus animal model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-200.
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