Carbonic anhydrase IX: An atypical target for innovative therapies in cancer

: Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed

Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer

Mast cells are important modifiers of prostate tumor microenvironment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system plays a non-redundant autocrine/paracrine role in the growth, vascularization and progression of prostate tumors. Accordingly, the FGF antagonist long pentraxin-3 (PTX3) and the PTX3-derived small molecule FGF-trap NSC12 have been shown to inhibit the growth and vascularization of different FGF-dependent tumor types, including prostate cancer. In this study, we show that recombinant FGF2 is able to cause mast cell recruitment in vivo in the Matrigel plug assay. Conversely, PTX3 overexpression in transgenic mice or treatment with the FGF inhibitor NSC12 result in a significant inhibition of the growth and vascularization of TRAMP-C2 tumor grafts, a murine model of prostate cancer, that were paralleled by a decrease of mast cell infiltrate into the lesion. These data confirm and extend previous observations about the capacity of mast cells to respond chemotactically to FGF2 stimulation and provide evidence about a relationship among mast cell recruitment, angiogenesis, and tumor growth in human prostate adenocarcinom

Viscoelastic Properties of Rapid Prototyped Magnetic Nanocomposite Scaffolds for Osteochondral Tissue Regeneration

Poly(ϵ-caprolactone) and poly(ethylene glycol) based magnetic nanocomposite scaffolds were fabricated using fused deposition modeling and stereolithography approaches, and a hybrid scaffold was obtained by combining these additive manufacturing technologies. Viscoelastic properties in compression were investigated at 37 °C, spanning a range frequency of four decades. Results suggest that poly(ϵ-caprolactone) and poly(ethylene glycol) based scaffolds adequately reproduce viscoelastic properties of subchondral bone and articular cartilage tissues, respectively. By combining fused deposition modeling and stereolithography it is possible to manufacture a hybrid scaffold suitable for osteochondral tissue regeneration. Poly(ϵ-caprolactone) and poly(ethylene glycol) based magnetic nanocomposite scaffolds were fabricated using fused deposition modeling and stereolithography approaches, and a hybrid scaffold was obtained by combining these additive manufacturing technologies. Viscoelastic properties in compression were investigated at 37 °C, spanning a range frequency of four decades. Results suggest that poly(ϵ-caprolactone) and poly(ethylene glycol) based scaffolds adequately reproduce viscoelastic properties of subchondral bone and articular cartilage tissues, respectively. By combining fused deposition modeling and stereolithography it is possible to manufacture a hybrid scaffold suitable for osteochondral tissue regeneration

Provably efficient offline reinforcement learning in regular decision processes

This paper deals with offline (or batch) Reinforcement Learning (RL) in episodic Regular Decision Processes (RDPs). RDPs are the subclass of Non-Markov Decision Processes where the dependency on the history of past events can be captured by a finite-state automaton. We consider a setting where the automaton that underlies the RDP is unknown, and a learner strives to learn a near-optimal policy using pre-collected data, in the form of non-Markov sequences of observations, without further exploration. We present RegORL, an algorithm that suitably combines automata learning techniques and state-of-the-art algorithms for offline RL in MDPs. RegORL has a modular design allowing one to use any off-the-shelf offline RL algorithm in MDPs. We report a non-asymptotic high-probability sample complexity bound for RegORL to yield an ε-optimal policy, which makes appear a notion of concentrability relevant for RDPs. Furthermore, we present a sample complexity lower bound for offline RL in RDPs. To our best knowledge, this is the first work presenting a provably efficient algorithm for offline learning in RDPs

Ten Years of CRISPRing Cancers In Vitro

Cell lines have always constituted a good investigation tool for cancer research, allowing scientists to understand the basic mechanisms underlying the complex network of phenomena peculiar to the transforming path from a healthy to cancerous cell. The introduction of CRISPR in everyday laboratory activity and its relative affordability greatly expanded the bench lab weaponry in the daily attempt to better understand tumor biology with the final aim to mitigate cancer's impact in our lives. In this review, we aim to report how this genome editing technique affected in the in vitro modeling of different aspects of tumor biology, its several declinations, and analyze the advantages and drawbacks of each of them

Cancer stem-like cells in uveal melanoma: novel insights and therapeutic implications

Uveal melanoma (UM) is the most common primary ocular tumor in the adult population. Even though these primary tumors are successfully treated in 90% of cases, almost 50% of patients ultimately develop metastasis, mainly in the liver, via hematological dissemination, with a median survival spanning from 6 to 12 months after diagnosis. In this context, chemotherapy regimens and molecular targeted therapies have demonstrated poor response rates and failed to improve survival. Among the multiple reasons for therapy failure, the presence of cancer stem-like cells (CSCs) represents the main cause of resistance to anticancer therapies. In the last few years, the existence of CSCs in UM has been demonstrated both in preclinical and clinical studies, and new molecular pathways and mechanisms have been described for this subpopulation of UM cells. Here, we will discuss the state of the art of CSC biology and their potential exploitation as therapeutic target in UM

Tumor angiogenesis revisited: Regulators and clinical implications

Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases

Gastric adenocarcinoma cutaneous metastasis arising at a previous surgical drain site: a case report

<p>Abstract</p> <p>Introduction</p> <p>Skin metastasis from internal carcinoma rarely occurs. It has an incidence of 0.7 to 9% and it may be the first sign of an unknown malignancy. However, it can also occur during follow-up.</p> <p>Case presentation</p> <p>A 90-year-old female patient was admitted to our surgical division with a diagnosis of anemia from a bleeding gastric adenocarcinoma. She underwent a gastric resection and Billroth II retrocolic Hofmeister/Finsterer reconstruction. She developed an enteric fistula, which needed a permanent abdominal drain until the 60^thpostoperative day. After 12 months she was readmitted to our division with subacute small bowel obstruction and an erythematous swelling on the right side of the abdomen. Biopsies characterized it as a cutaneous metastasis from the gastric adenocarcinoma. No surgical therapy was performed given her poor clinical condition.</p> <p>Conclusion</p> <p>Skin metastasis from carcinomas of the upper gastrointestinal tract is very rare. Persisting erythematous nodules must be biopsied in order to diagnose cutaneous metastases and to recognize them early and start prompt therapy with anti-tumour agents before the occurrence of massive visceral metastases.</p

The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation

Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1-10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1-100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms