High-dose vitamin C enhances cancer immunotherapy.

Vitamin C (VitC) is known to directly impair cancer cell growth in preclinical models, but there is little clinical evidence on its antitumoral efficacy. In addition, whether and how VitC modulates anticancer immune responses is mostly unknown. Here, we show that a fully competent immune system is required to maximize the antiproliferative effect of VitC in breast, colorectal, melanoma, and pancreatic murine tumors. High-dose VitC modulates infiltration of the tumor microenvironment by cells of the immune system and delays cancer growth in a T cell-dependent manner. VitC not only enhances the cytotoxic activity of adoptively transferred CD8 T cells but also cooperates with immune checkpoint therapy (ICT) in several cancer types. Combination of VitC and ICT can be curative in models of mismatch repair-deficient tumors with high mutational burden. This work provides a rationale for clinical trials combining ICT with high doses of VitC.

Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

OBJECTIVE: Evidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreductive surgery (MI-SCS). METHODS: Cisplatin levels were assessed at 0, 20, 40, 60, and 120 minutes in: 1) blood samples, 2) peritoneal perfusate, and 3) peritoneal biopsies at the end of HIPEC. Median Cmax has been used to identify women with high and low drug levels. Progression-free survival (PFS) was calculated as the time elapsed between SCS+HIPEC and secondary recurrence or last follow-up visit. RESULTS: Nine (45.0%) women received MI-SCS, and 11 (55.0%) O-SCS. At 60 minutes, median cisplatin Cmax in peritoneal tissue was higher in patients treated with MI-SCS compared to O-SCS (Cmax=8.262 µg/mL vs. Cmax=4.057 µg/mL). Furthermore, median cisplatin plasma Cmax was higher in patients treated with MI-SCS compared to O-SCS (Cmax=0.511 vs. Cmax=0.254 µg/mL; p-value=0.012) at 120 minutes. With a median follow-up time of 24 months, women with higher cisplatin peritoneal Cmax showed a longer PFS compared to women with low cisplatin peritoneal levels (2-years PFS=70% vs. 35%; p-value=0.054). CONCLUSIONS: We demonstrate for the first time that minimally invasive route enhances cisplatin peritoneal tissue uptake during HIPEC, further evaluations are needed to confirm the correlation between peritoneal cisplatin levels after HIPEC and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01539785.

High Penetration of Paclitaxel in Abdominal Wall of Rabbits after Hyperthermic Intraperitoneal Administration of Nab-Paclitaxel Compared to Standard Paclitaxel Formulation.

PURPOSE: Paclitaxel (PTX) is currently used in combination with cisplatin for Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis. Albumin-bound PTX is a promising new drug for HIPEC because of its easy solubility in aqueous perfusion medium and possibly because of the tendency of albumin to cross physiological barriers and accumulate in tumor tissue. METHODS: We tested the feasibility of using nab-paclitaxel in rabbits treated by HIPEC for 60 min compared with the classical formulation at an equivalent PTX dose. Samples of perfusate and blood were collected at different time points and peritoneal tissues were collected at the end of perfusion. PTX concentrations were determined by HPLC. The depth of paclitaxel penetration through the peritoneal barrier was assessed by mass spectrometry imaging. RESULTS: PTX after nab-paclitaxel treatment penetrated up to 0.63 mm in the peritoneal wall, but after CRE-paclitaxel, it was not detectable in the peritoneum. Moreover, the peritoneal concentration after nab-paclitaxel was five times that after paclitaxel classical formulation. Despite the high levels reached in the peritoneum, systemic exposure of PTX was low. CONCLUSIONS: Our results show that nab-paclitaxel penetrates into the abdominal wall better than CRE-paclitaxel, in terms of effective penetration and peritoneal tissue concentration.

A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: MicroRNAs (miRNAs) are small, noncoding RNA molecules that can be down- or upregulated in colorectal cancer and have been associated to prognosis and response to treatment. We studied miRNA expression in tumor biopsies of patients with rectal cancer to identify a specific "signature" correlating with pathological complete response (pCR) after neoadjuvant chemoradiotherapy. METHODS AND MATERIALS: A total of 38 T3-4/N+ rectal cancer patients received capecitabine-oxaliplatin and radiotherapy followed by surgery. Pathologic response was scored according to the Mandard TRG scale. MiRNA expression was analyzed by microarray and confirmed by real-time Reverse Transcription Polymerase Chain Reaction (qRT-PCR) on frozen biopsies obtained before treatment. The correlation between miRNA expression and TRG, coded as TRG1 (pCR) vs. TRG >1 (no pCR), was assessed by methods specifically designed for this study. RESULTS: Microarray analysis selected 14 miRNAs as being differentially expressed in TRG1 patients, and 13 were confirmed by qRT-PCR: 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909∗, miR-630, miR-765) were significantly upregulated in TRG1 patients, 2 (miR-1274b, miR-720) were downexpressed. MiR-622 and miR-630 had a 100% sensitivity and specificity in selecting TRG1 cases. CONCLUSIONS: A set of 13 miRNAs is strongly associated with pCR and may represent a specific predictor of response to chemoradiotherapy in rectal cancer patients.

E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models.

Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation.

Contemporary pre-clinical development of anticancer agents--what are the optimal preclinical models?

The successful identification of novel effective anticancer drugs is largely dependent on the use of appropriate preclinical experimental models that should possibly mimic the complexity of different cancer diseases. The huge number of targets suitable for the design of new anticancer drugs is producing hundreds of novel molecules that require appropriate experimental models to investigate their mode of action and antitumour activity in order to select for clinical investigation the ones with higher chances of being clinically effective. However, our ability to predict the clinical efficacy of a new compound in the clinic based on preclinical data is still limited. This paper overviews the in vitro/in vivo preclinical systems that are currently used to test either compounds with an unknown mechanism of action or compounds designed to hit cancer-specific or cancer-related molecular targets. Examples of experimental models successfully used to identify novel compounds are provided. Xenografts are still the most commonly used in vivo models in drug development due to their high degree of reproducibility and because, in some cases, particularly when orthotopically transplanted, they maintain several biological properties of the human tumours they derive from. Genetic models are very useful for target validation, but are often not sufficiently reproducible to be used for drug evaluation. The variety of animal models can be effectively used to optimally test drugs that presumably act by a defined mode of action, but final success is highly dependent on the ability of drug development teams to integrate different expertises such as biology, chemistry, pharmacology, toxicology and clinical oncology into a clever and well orchestrated plan that keeps in consideration both the complexity of cancer diseases, involving alterations of different pathways, and the complexity of drugs whose pharmacological properties are crucial to obtain the desired effects.

Modulation of response to cancer chemotherapeutic agents by diet constituents: is the available evidence sufficiently robust for rational advice for patients?

BACKGROUND: Patients who are diagnosed with cancer want advice on how they may alter their diet or which diet supplements they should take to augment chemotherapy. METHODS: We conducted a review of the literature mostly from the last 15 years on the interaction between dietary constituents and antineoplastic therapy in preclinical rodent models and in clinical trials. RESULTS: Studies have explored the effect of predominantly antioxidant vitamins and folate on efficacy or toxicity mediated by cisplatin and anthracyclins. Cisplatin toxicity in rodents was ameliorated by vitamin E. The design of clinical studies of dietary agents in combination with cytotoxic agents has been very heterogeneous and results have been inconclusive. CONCLUSIONS: Whilst preclinical experiments hint at a potential benefit of certain dietary agents, the evidence emanating from clinical studies does not allow firm conclusions to be made. Future studies should explore physiological doses of dietary agent and include pharmacokinetic and pharmacodynamic measurements.

Use of cancer chemopreventive phytochemicals as antineoplastic agents.

A lot of information has been gathered on cellular mechanisms by which chemopreventive phytochemicals, such as curcumin (a spice in curry) or epigallocatechin gallate (extracted from tea), interfere with carcinogenesis. A comparison of this knowledge with what we know about molecularly targeted chemotherapeutic agents suggests that it might be worthwhile to investigate the usefulness of such phytochemicals in the treatment of established malignant diseases. Phytochemicals use a plethora of antisurvival mechanisms, boost the host's anti-inflammatory defence, and sensitise malignant cells to cytotoxic agents. The restricted systemic availability of agents such as curcumin and epigallocatechin gallate, needs to be taken into account if they are to be developed as cochemotherapeutic drugs.

Preclinical and clinical results with the natural marine product ET-743.

ET-743 (Yondelis, trabectedin) is a natural marine product with antitumour properties derived from the tunicate Ecteinascidia turbinata. ET-743 binds to the N2 position of guanine in the minor groove of DNA with some degree of sequence specificity, altering the transcription regulation of induced genes. Cells that are deficient in nucleotide excision repair, hypersensitive to UV rays, cisplatin and conventional alkylating agents, are resistant to ET-743. This is a unique property of ET-743 and is of potential importance for the drug activity when administered alone or in combination with other drugs. ET-743 showed striking antitumour activity against sensitive and resistant human xenografts. The dose-limiting toxicities in animal models, hepatobiliary events, were of concern, but the pattern of the reversibility noted in monkeys and the evidence of a positive therapeutic index in tumour-bearing nude mice prompted its clinical development. The Phase I programme investigated different schedules of administration, with the dose-limiting toxicities being neutropenia and fatigue. As anticipated in the preclinical models, reversible non-cumulative transaminitis was a prevalent finding from one-third of the maximum tolerated dose level; long-lasting objective responses in pretreated resistant patients were noted, including consistent efficacy data in mesenchymal tumours. The Phase II data for ET-743 administered as a single agent has established a clinical role for the compound in advanced pretreated soft tissue sarcoma and a promising potential in pretreated ovarian and breast cancer. ET-743 combined with other drugs (i.e., cisplatin, paclitaxel or doxorubicin) showed more than additive effects in several preclinical systems and initial clinical results (e.g., a combination of ET-743 with cisplatin) appear to confirm the preclinical findings. In summary, ET-743 is a new drug with a novel mode of action, which has demonstrated activity in human tumours resistant to the available anticancer drugs. Further comparative studies are needed to define the role of ET-743 alone or in combination in cancer chemotherapy.