BRAF- and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress

Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID 50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma)

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Background: reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. Methods: to test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. Results: correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. Conclusions: in summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue

An Association of Cancer Physicians' strategy for improving services and outcomes for cancer patients.

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.The ACP is very grateful to all of its members who have expressed views on the development of the strategy and to the sponsors of our workshops and publications, especially Cancer Research UK and Macmillan Cancer SupportThis is the final version of the article. It was first available from Cancer Intelligence via http://dx.doi.org/10.3332/ecancer.2016.60

Targeted therapeutic approaches for hormone-refractory prostate cancer

Prostate cancer is one of the leading causes of cancer related death in men, and remains incurable in the metastatic setting. Despite the initial response to androgen deprivation, the disease gradually progresses to a hormone-refractory state due to cumulative genetic alterations in tumour cells or the microenvironment. Docetaxel represents the first chemotherapeutic agent with a small survival benefit for metastatic hormone-refractory prostate cancer (HRPC). In an attempt to improve survival benefit, several novel drugs targeting specific pathways involved in cell signaling, proliferation, angiogenesis, apoptosis and immune modulation are currently under investigation either as single agents or in combination with cytotoxic drugs. Clinical trials evaluate the inhibition of prostate cancer cells growth by targeting the nuclear receptor of vitamin D alongside cytotoxic therapy. Angiogenesis inhibitors as well as epidermal growth factor receptor blockage are also under clinical investigation in several combinations. Immunomodulatory agents and autologous dendritic cells or allogenic whole cell vaccines have progressed up to phase III trials. New drugs targeting bone microenvironment or apoptotic and proliferation pathways may enhance antitumour activity of chemotherapy in HRCP. Given the complexity of mechanisms underlying prostate cancer progression, future therapeutic strategies should rely on multidisciplinary approaches, thus exploiting newer molecular targets in concert with immunotherapy and cytotoxic chemotherapy. Here, we review the latest clinical evidence regarding the use of novel agents in HRPC. (C) 2009 Elsevier Ltd. All rights reserved

Heat shock protein inhibitors and vaccines as new agents in cancer treatment

Background: Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct holding and folding in human cells. At the same time they present implications in tumor cell proliferation, differentiation, matrix invasion, angiogenesis, metastasis and cell death. They also possess the ability to present tumor molecules to the immune system and elicit an immune response. New agents targeting HSP, as anticancer treatment, are under clinical evaluation. Objective: The aim of this review is to explore the role of HSP90 inhibitors as anticancer agents as well as to evaluate the benefit from the use of autologous HSP vaccines in both the adjuvant setting and first-line treatment. Methods: The latest evidence regarding the use of geldanamycin analogues or newer water-soluble and synthetics molecules that inhibit the binding of HSP90 to client proteins was reviewed. Immunization using tumor-derived HSP in several cancer types was also evaluated. Conclusions: HSP90 inhibitors represent a promising therapeutic option although further evaluation in larger clinical trials is needed. On the other hand, HSP vaccination has already an established role in our armory against cancer

Tuberculosis associated with triplet therapy for lung cancer

We report the first case of TB associated with triplet therapy (chemotherapy and immunotherapy concurrently) for lung cancer, developing just 44 days after treatment initiation. We feel that several important learning points arise from the discussion that are likely to be very relevant to the broad readership of Thorax, and have important clinical and scientific implications. In the three discussion paragraphs, we highlight that: 1) Triplet therapy is now standard first-line treatment for inoperable lung cancer. 2) TB reactivation is increasingly recognised as an adverse effect of immune checkpoint inhibition, but sending diagnostic samples is critical to avoid a missed diagnosis. 3) These insights from novel cancer immunotherapies are challenging the traditional views of the host-pathogen interaction in TB, with wide implications for future control strategies. We propose that the cases reported in the literature are likely to be the tip of the iceberg as most people with lung cancer managed with antiprogrammed death-1 agents who develop new lung lesions will be treated with standard antibiotics and then palliated when they do not respond

Bevacizumab-Induced Hypertension Pathogenesis and Management

Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general

The role of mTOR in the management of solid tumors: An overview

Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA and ribosome with a regulatory effect on cell cycle progression, cellular proliferation and growth. TOR genes were discovered rather serendipitously while investigating the cause of resistance to immunosuppressant rapamycin in yeast. In normal cells, mTOR controls brilliantly the load of signals from its effectors resulting in a normal cell function. On the contrary, in various diseases and mainly in cancer this balance is lost due to mutations or overactivation of upstream pathways leading to a persistent proliferation and tumor growth. What makes mTOR attractive to researchers seems to be its key position which is on the crossroad of various signal pathways (Ras, PI3K/Akt, TSC, NF-kappa B) towards mRNA, ribosome, protein synthesis and translation of significant molecules, the uncontrolled production of which may lead to tumor proliferation and growth. Inhibition of mTOR by rapamycin (a natural product) or its analogs aims to prevent the deleterious effects of the abnormal signaling, regardless at which point of the signal pathway has the abnormality launched. Here, we will review the physiological functions of mTOR, its association to carcinogenesis and the latest evidence regarding the use of mTOR inhibitors in cancer treatment as well as future trends and aims of research. (C) 2008 Elsevier Ltd. All rights reserved

Erlotinib-Induced Skin Rash in Patients with Non-Small-Cell Lung Cancer: Pathogenesis, Clinical Significance, and Management

The human epidermal growth factor receptor (EGFR) signaling is overexpressed in many solid malignancies, making it an appealing target for biologic agents. A number of agents that target this receptor are in use or in development. A specific adverse effect common to this class of agents is an acneiform-like skin rash that has been related to EGFR inhibition in the skin. Little is known about the etiology of this rash, and there are no clear evidence-based management recommendations. Findings suggest that there is a relationship between the development of rash and response and/or survival, making rash a potential surrogate marker of activity. This review summarizes and updates the current knowledge of the clinical presentation, etiology, and predictive and prognostic value of erlotinib-induced skin rash and establishes a treatment strategy to help treat dermatologic adverse events and allow patients to continue therapy without dose interruption or drug discontinuation