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Background: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated., Patients and Methods: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m 2 ) and gemcitabine (1000 mg/m 2 ). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed., Results: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events., Conclusions: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents., Competing Interests: Disclosure MT: consultancy/advisory role with Advance Medical, AstraZeneca, Bristol-Myers Squibb (BMS), EcoR1 Capital, Elicio Therapeutics, FibroGen, Inc., GlaxoSmithKline, Immunovia, ISPEN, Karyopharm Therapeutics, Merck & Co., Inc., and Swedish Orphan Biovitrum; research funding from Celgene and Halozyme; other relationship(s) with Astellas Pharma Global Development, Inc. (DSMC). D-YO: consultancy/advisory role with ASLAN, AstraZeneca, Bayer, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho, and Zymeworks; research funding from Array, AstraZeneca, and Eli Lilly. JT: consultancy/advisory role with Array Biopharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai, F. Hoffmann-La Roche Ltd, Foundation Medicine, Genentech, Inc., Genmab A/S, HalioDX SAS, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, Merck Sharp & Dohme (MSD), Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics LLC, an AbbVie Company, ProteoDesign SL, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, Seagen, Seattle Genetics, Servier, Symphogen, Taiho, and VCN Biosciences. MR: honoraria from Baxalta, Celgene, and Shire; consultancy/advisory role with Baxalta, Celgene, Eli Lilly, Novartis, Novocure, Pfizer, and Shire; research funding to Institution from Celgene; travel expenses from Celgene, AstraZeneca; other relationship(s) with AstraZeneca, Boston Pharmaceuticals, and Celgene. EVC: consultancy/advisory role with AstraZeneca, Bayer, BMS, Celgene, Lilly, MSD, Merck DGaA, Novartis, Roche, and Servier; research funding from Amgen, Bayer, Boehringer Ingelheim, BMS, Celgene, Ipsen, Lilly, Merck, Merck KGaA, Novartis, Roche, and Servier. AH: consultancy/advisory role with AbbVie, Ipsen, Merck, and Novartis; research funding from Ipsen. D-TW: speakers' bureau for AstraZeneca, BMS, Celgene, Eisai, Falk, Ipsen, Novartis, Roche, Servier, Shire Baxalta, and Sirtex; travel expenses from Bayer Health Pharma, Celgene, Ipsen, Novartis, and Sirtex. NS: honoraria from Eli Lilly, Merck Serono, MSD Oncology, and Pierre Fabre; consultancy/advisory role with AstraZeneca, Pfizer, and Servier; research funding from AstraZeneca, BMS, and Pfizer; travel expenses from AstraZeneca, BMS, Eli Lilly, Merck, and Roche. J-BB: honoraria from Amgen, AstraZeneca, Bayer, Celgene, Merck Serono, Mundipharma, Pierre Fabre, Roche, Sanofi, and Servier; consultancy/advisory role with Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, and Servier; travel expenses from Amgen, Bayer, Celgene, Merck Serono, Roche, Sanofi, and Servier. H-MC: research funding from Astellas, Halozyme, Pharmacyclics LLC, an AbbVie Company, Senhwa Biosciences, Taiho Oncology. JM: consultancy/advisory role with Advance Medical, AstraZeneca, Bayer, Pierre-Fabre, Roche, Sanofi, Servier, Shire, and Sirtex; research funding from Amgen, Biocartis, Incyte, Merck, Nanostring, and Servier; patents, royalties, or other intellectual property with GAIS-42-patent P5020EP00. RG: honoraria from AAA, Amgen, Bayer, BMS, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche, and Sanofi; research funding from ARMO Biosciences, AstraZeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics LLC, an AbbVie Company, Boston Biomedicals, Merck, MSD, Amgen, Sanofi, Bayer, BMS, Boehringer, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, PharmaMar; travel expenses from Ipsen, Merck, Novartis, and Servier. SL: consultancy/advisory role with Amgen, Lilly, Merck Serono, and Servier; research funding from Amgen and Merck Serono; speakers' bureau for BMS, Lilly, Merck Serono, Roche, and Servier. LMC: employment with Oregon Health & Science University; honoraria from Aduro Biotech, AstraZeneca, Carisma Therapeutics, Inc., Cell Signaling Technologies, CytomX Therapeutics, Inc., Jackson Laboratories, Seattle Genetics, Syndax Pharmaceuticals, Inc., Verseau Therapeutics, Inc., and Zymeworks, Inc.; consultancy/advisory role with Carisma Therapeutics Inc., Cell Signaling Technologies, CytomX Therapeutics, Inc., Syndax Pharmaceuticals, Inc., Verseau Therapeutics, Inc., and Zymeworks, Inc.; research funding (for profit) Acerta Pharma, Deciphera Pharmaceuticals, Innate Pharma, Roche Glycart and Parker Institute for Immunotherapy, and Syndax Pharmaceuticals, Inc.; patents, royalties, or other intellectual property with Oregon Health & Science University; other relationship(s) with Reagent from Reagent support from: Acerta Pharma, LLC, Cell Signaling Technologies, Deciphera Pharmaceuticals, Genentech/Roche Glycart AG, NanoString Technologies, Inc., Plexxikon, Inc, and Syndax Pharmaceuticals. LF: research funding from AbbVie, Bavarian Nordic, BMS, Dendreon, Janssen, Merck, Roche/Genentech. GC: employment with Pharmacyclics LLC, an AbbVie Company; stock ownership in AbbVie. DJ: employment with Pharmacyclics LLC, an AbbVie Company; leadership role with Pharmacyclics LLC, an AbbVie Company; stock ownership in AbbVie; patents, royalties, or other intellectual property with Pharmacyclics LLC, an AbbVie Company. TM: consultancy/advisory role with Advance Medical HCMS, Baxter, BioLineRX Ltd, Celgene SLU, Eisai, Genzyme, Incyte, IPSEN Pharma Lab. Menarini, Lab. Servier, Lilly, QED Therapeutics, MSD, Prime Oncology EU, QED Therapeutics Inc., Sanofi-Aventis; research funding from Agios, ASLAN, AstraZeneca, Bayer, Celgene, Genentech, Hallozyme, Immunomedics, Lilly, Merimarck, Millenium, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, and Roche; travel expenses from Servier and Incyte. LCT has declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy ( n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples ( n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity ( P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family ( P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors., (Copyright © 2018, American Association for the Advancement of Science.)

Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib by failing to upregulate Noxa, a pro-apoptotic sensitizer BH3-only protein that acts by displacing Bim, a pro-apoptotic Bax/Bak-activator protein. Surprisingly, despite their resistance, spheroids also upregulated Bim and thereby acquired sensitivity to ABT-737, an inhibitor of anti-apoptotic Bcl-2 molecules. Analysis using BH3 profiling confirmed that spheroids acquired a dependence on anti-apoptotic Bcl-2 proteins and were 'primed for death'. We then studied spheroids grown from actual mesothelioma. ABT-737 was active in spheroids grown from those tumors (5/7, ∼70%) with elevated levels of Bim. Using immunocytochemistry of tissue microarrays of 48 mesotheliomas, we found that most (33, 69%) expressed elevated Bim. In conclusion, mesothelioma cells in 3D alter the expression of Bcl-2 molecules, thereby acquiring both apoptotic resistance and sensitivity to Bcl-2 blockade. Mesothelioma tumors ex vivo also show sensitivity to Bcl-2 blockade that may depend on Bim, which is frequently elevated in mesothelioma. Therefore, mesothelioma, a highly resistant tumor, may have an intrinsic sensitivity to Bcl-2 blockade that can be exploited therapeutically.

Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. Aberrant activation of WNT signaling is implicated in lung carcinogenesis. EMX2, a human homologue of the Drosophila empty spiracles gene is a homeodomain-containing transcription factor. The function of EMX2 has been linked to the WNT signaling pathway during embryonic patterning in mice. However, little is known about the role of EMX2 in human tumorigenesis. In this study, we found that EMX2 was dramatically downregulated in lung cancer tissue samples and this downregulation was associated with methylation of the EMX2 promoter. Restoration of EMX2 expression in lung cancer cells lacking endogenous EMX2 expression suppressed cell proliferation and invasive phenotypes, inhibited canonical WNT signaling, and sensitized lung cancer cells to the treatment of the chemo cytotoxic drug cisplatin. On the other hand, knockdown of EMX2 expression in lung cancer cells expressing endogenous EMX2 promoted cell proliferation, invasive phenotypes and canonical WNT signaling. Taken together, our study suggests that EMX2 may have important roles as a novel suppressor in human lung cancer.

To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)-HPV16). We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14-HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14-HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease.

There is increasing clinical and experimental evidence that inflammation and cancer are causally linked. Much progress has been made in understanding how inflammatory cells contribute to cancer development; however, it is still largely unknown which molecular mechanisms are responsible for initiation and maintenance of chronic inflammation associated with developing neoplasms. This review will discuss how the adaptive and innate immune systems interact during physiological and chronic inflammation, with a focus on studies revealing new insights into the role of adaptive immune cells as important regulators of chronic inflammation-associated carcinogenesis. We will speculate on whether current knowledge about the dysregulated interplay between adaptive and innate immunity during chronic inflammatory disorders might be useful in understanding and targeting the underlying mechanisms of chronic inflammation-associated neoplastic progression.

The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.

Extracellular metal-dependent proteinases regulate cell behavior by remodeling stromal and cell surface proteins, thereby influencing cell recruitment, cell shape, motility, proliferation, survival, genomic (in)stability, and differentiation. In recent years, the importance of proteinase-induced signaling has been underscored by evidence that altered regulation of cell-extracellular matrix and cell-cell interactions by proteinases can contribute, in a causal manner, to neoplastic progression.

Expression of HPV16 early region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid tumors, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-4 (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.

Embryonic development and tumor progression both require the exquisite coordination of programs for extracellular matrix (ECM) formation and remodeling, and those for angiogenesis and vascular development. Without a vascular supply the normal tissue or tumor is limited in size and organization. Without ECM remodeling the alteration of tissue and tumor boundaries and cellular migrations are limited. Recent insights into the molecular mechanisms regulating the extracellular environment of the growing embryonic tissue or tumors have implicated proteases, the matrix metalloproteinases (MMPs) in particular, in both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processes. This review focuses on the roles that MMPs play in regulating three processes in which both proteolysis and vascular development are tightly coordinated: embryo implantation, bone development and tumor progression.

The epidemiology and histopathology of human cancers and studies of animal models of tumorigenesis have led to a widely-accepted notion that multiple genetic and epigenetic changes have to accrue for the successful development of a malignant phenotype. Tumor growth and expansion requires an ability not only to proliferate, but also to down-modulate cell death (apoptosis) and activate angiogenesis to produce a tumor neovasculature. This review will describe the interplay between apoptosis and proliferation, as well as the characteristics of the angiogenic phenotype in two transgenic mouse models of multi-step tumorigenesis, namely, pancreatic islet cell carcinomas and squamous cell carcinomas of the skin.

Reproducible multi-stage progression to invasive squamous carcinoma of the epidermis has been achieved in transgenic mice expressing the HPV16 early-region genes, including the E6/E7 oncogenes, under the control of the human keratin-14 promoter/enhancer. Although 100% of K14-HPV16 transgenic animals develop hyperplastic and/or dysplastic lesions in several inbred backgrounds, including C57BL/6, BALB/c, and SSIN/SENCAR, only mice backcrossed into the FVB/n background progress to malignant squamous cell carcinomas of two pathological grades, well differentiated and moderate/poorly differentiated (WDSC or MPDSC, respectively), each displaying characteristic patterns of malignant behavior. WDSCs typically arise within the epidermis of the ear and invade deeply into the underlying dermis but fail to metastasize, whereas MPDSCs develop on the chest and truncal skin and invariably metastasize to regional lymph nodes. The transition to the malignant state, in 21% of FVB/n transgenic mice, is characterized by alteration of the repertoire of keratin intermediate filament proteins expressed within neoplastic epidermis, such that WDSCs maintain expression of keratins common to terminally differentiating stratified keratinocytes (K10), whereas MPDSCs are distinguished from WDSCs by activation of embryonic and mucosal keratins (K13, K8, and K19). Precursor hyperplastic and dysplastic lesions are characterized by a progressively increased proliferative index, striking morphological alterations in keratinocyte cell-cell and cell-matrix interactions, and extensive remodeling of the underlying dermal stroma. Remarkably, this extensive stromal remodeling, which may facilitate both angiogenesis and eventual tumor cell invasion, develops early at the dysplastic stage in all animals well before malignant conversion.

Proteolytic remodeling of the extracellular matrix is an important aspect of the creation and progression of cancer. Matrix metalloproteinases are important at several points during multi-stage neoplastic progression in tumor cells and responding blood vessels, inflammatory cells and stroma.

Transforming growth factor beta (TGF-beta), a multifunctional polypeptide growth factor, regulates the expression of many genes critical to cell cycle progression, such as members of the jun gene family which encode components of the transcription factor complex AP-1. The transforming proteins encoded by the early region 1A of adenovirus12 (Ad.12-E1A) abrogate some of the cellular responses to TGF-beta as well as affecting, differentially, the expression of cellular jun genes. Our data demonstrate that expression of Ad.12-E1A in rat 3Y1 fibroblast cells inhibits induction of junB by TGF-beta 1 while not altering the regulation of junB by phorbol ester or serum. Regulation of c-jun gene expression by TGF-beta 1, phorbol ester, and serum is not appreciably altered by the expression of Ad.12-E1A. Inhibition of TGF-beta induced junB expression is not due to a defect in TGF-beta/receptor interaction on Ad.12-E1A transformed cells and is not observed in other isotypic fibroblast cells transformed by SV40 or polyomavirus. These data suggest that multiple, independent, intracellular signal transduction pathways exist which mediate genomic responses to TGF-beta. Cellular expression of Ad.12-E1A-12S gene products results in selective disruption of some TGF-beta 1 signaling cascades and not those activated by phorbol ester or serum. These data further suggest that some cellular targets which mediate TGF-beta 1 action may also be unique targets of action for the E1A-12S transforming protein of adenovirus12.