Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.

/pdf/gut-brain-axis-and-the-microbiota-3ksluuopxy.pdf

Gut/brain axis and the microbiota

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.

/pdf/rethinking-ovarian-cancer-ii-reducing-mortality-from-high-43u6pur2b0.pdf

Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer

The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.

Engineered T cells: the promise and challenges of cancer immunotherapy

Tumor relapse and metastasis are the primary causes of poor survival rates in patients with advanced cancer despite successful resection or chemotherapeutic treatment. A primary cause of relapse and metastasis is the persistence of cancer stem cells (CSCs), which are highly resistant to chemotherapy. Although highly efficacious drugs suppressing several subpopulations of CSCs in various tissue-specific cancers are available, recurrence is still common in patients. To find more suitable therapy for relapse, the mechanisms underlying metastasis and drug-resistance associated with relapse-initiating CSCs need to be identified. Recent studies in circulating tumor cells (CTCs) of some cancer patients manifest phenotypes of both CSCs and epithelial-mesenchymal transition (EMT). These patients are unresponsive to standard chemotherapies and have low progression free survival, suggesting that EMT-positive CTCs are related to co-occur with or transform into relapse-initiating CSCs. Furthermore, EMT programming in cancer cells enables in the remodeling of extracellular matrix to break the dormancy of relapse-initiating CSCs. In this review, we extensively discuss the association of the EMT program with CTCs and CSCs to characterize a subpopulation of patients prone to relapses. Identifying the mechanisms by which EMT-transformed CTCs and CSCs initiate relapse could facilitate the development of new or enhanced personalized therapeutic regimens.

/pdf/emt-ctcs-and-cscs-in-tumor-relapse-and-drug-resistance-19w3xy71zc.pdf

EMT, CTCs and CSCs in tumor relapse and drug-resistance

Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear β-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.

/pdf/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-4ghyhid9jq.pdf

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

Although initially responsive to chemotherapy, many patients with ovarian cancer subsequently develop relapsed and potentially fatal metastatic disease, which is thought to develop from cancer stem cells (CSCs) that are relatively resistant to conventional therapy. Here, we show that CSCs express a type I receptor tyrosine kinase-like orphan receptor (ROR1), which is expressed during embryogenesis and by many different cancers, but not normal postpartum tissues. Ovarian cancers with high levels of ROR1 had stem cell-like gene-expression signatures. Furthermore, patients with ovarian cancers with high levels of ROR1 had higher rates of relapse and a shorter median survival than patients with ovarian cancers that expressed low-to-negligible amounts of ROR1. We found that ROR1-positive (ROR1+) cells isolated from primary tumor-derived xenografts (PDXs) also expressed aldehyde dehydrogenase 1 (ALDH1) and had a greater capacity to form spheroids and to engraft immune-deficient mice than did ROR1-negative (ROR1Neg) ovarian cancer cells isolated from the same tumor population. Treatment with UC-961, an anti-ROR1 mAb, or shRNA silencing of ROR1 inhibited expression of the polycomb ring-finger oncogene, Bmi-1, and other genes associated with the epithelial–mesenchymal transition. Moreover, shRNA silencing of ROR1, depletion of ROR1+ cells, or treatment with UC-961 impaired the capacity of ovarian cancer cells to form spheroids or tumor xenografts. More importantly, treatment with anti-ROR1 affected the capacity of the xenograft to reseed a virgin mouse, indicating that targeting ROR1 may affect CSC self-renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which contributes to their capacity to form tumors, making ROR1 a potential target for the therapy of patients with ovarian cancer.

https://www.pnas.org/content/pnas/111/48/17266.full.pdf

Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy.

A6 Peptide Is Selectively Cytotoxic For Chronic Lymphocytic Leukemia Cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. It is characterized by the clonal expansion of CD5+CD23+ B cells in blood, marrow, and second lymphoid tissues. Survival of CLL cells are supported by cells within the tissue microenvironment and by signals from the extracellular matrix, which in part are mediated via interactions with CD44, a surface glycoprotein that is expressed by CLL B cells and by putative cancer stem cells. CD44 interacts with other surface and cytosolic proteins expressed by CLL cells such as CD38, CD49d, MMP9 and ZAP-70, which enhanced signaling leading to growth or survival of CLL cells. We found that a mAb specific for CD44 was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. It could induce CLL cells that expressed the zeta-associated protein of 70 kDa (ZAP-70) to undergo caspase-dependent apoptosis (Proc Natl Acad Sci, USA 2013, PMID: 23530247). The cytotoxic effect of this mAb was not mitigated when the CLL cells were co-cultured with mesenchymal stromal cells (MSCs), suggesting that targeting CD44 may provide an effective approach for anti-cancer therapy.

A6 is an 8-amino acid peptide (Ac-KPSSPPEE-Am) that binds to the CD44 receptor within a region of the ligand-binding domain and induces anti-metastatic and anti-migration activity against a variety of cancers including ovarian, lung, and breast cancers. In this study we examined the cytotoxic effects and explored mechanism of A6 peptide against multiple CLL patient samples.

We found that A6 peptide exhibits a significant cytotoxic effect against CLL patient samples (N=22) in vitro while having negligible toxicity against healthy patient B cell samples (N=6). A6 also exhibits cytotoxic effects against CLL cells in a dose dependent manner. More importantly, we found that A6 is able to down-modulate CD44 expression, leading to down regulation of CD44-associated proteins (e.g. ZAP-70). Because ZAP-70 can directly enhance BCR signaling, reduction of ZAP-70, following A6 treatment resulted in attenuation of intracellular [Ca2++] flux after IgM ligation, which is an indicator of decrease in BCR signaling. Moreover, A6 exhibits significantly greater direct cytotoxicity for CLL cells (p=0.029) that express ZAP-70 than for CLL cells that were ZAP-70 negative. We transplanted primary ZAP-70 positive CLL patient samples (N=2) into the peritoneal cavity of immunodeficient mice. Intraperitoneal treatment with 300 mg/kg of A6 peptide twice daily for 7 days resulted in a significant reduction of CLL burden (90% and 64.2%) compared to PBS treated control groups. No significant adverse effects were observed. A6 peptide has been very well-tolerated in clinical trials with no clearly identifed systemic adverse events in patients with solid tumors who have been treated to date (N = 40). Thus, A6 presents a promising therapeutic agent not only against CLL but also against CD44 expressing cancer stem cells.

Citation Format: Hsien Lai, Suping Zhang, Christina Wu, Liguang Chen, Grace Liu, RongRong Wu, Fitzgerlad Lao, Jian Yu, Laura Rassenti, Michael Choi, Stephen Howell, Malcolm Finlayson, Thomas Kipps. Selective cytotoxicity of A6 peptide against ZAP-70 expressing CLL B-cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 950. doi:10.1158/1538-7445.AM2014-950

Abstract 950: Selective cytotoxicity of A6 peptide against ZAP-70 expressing CLL B-cells

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Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy.

A6 Peptide Is Selectively Cytotoxic For Chronic Lymphocytic Leukemia Cells

Abstract 950: Selective cytotoxicity of A6 peptide against ZAP-70 expressing CLL B-cells