The effects of anti-IL-6 therapy in advanced ovarian cancer

PhDIL-6 is a pleiotropic cytokine that has a significant role in inflammatory processes. In relation to ovarian cancer biology there is emerging evidence that it mediates processes relating to tumour growth, invasion, angiogenesis and chemo-resistance that lead to disease with poor prognosis. The aim of this thesis was to evaluate the efficacy and mechanism of action of an anti-human IL-6 antibody, CNTO328, in ovarian cancer. These aims were achieved with a clinical trial that was conducted in parallel with pre-clinical experiments. 18 patients with advanced platinum-resistant ovarian cancer were treated with CNTO328 in a phase II clinical trial. One patient had a partial response and seven patients attained stable disease at the end of the initial 6-week study period with correlations seen between clinical benefit and baseline levels of CRP, β2- microglobulin, TNF-α, IL-8 and VEGF. Four patients completed 6 months of treatment and had significantly decreased plasma CCL2 and increased sgp130 concentrations. Furthermore, immunohistochemical analysis of diagnostic biopsies suggested that clinical benefit was related to a lower macrophage infiltrate and increased stromal expression of IL-6, IL-6 receptors and SOCS3. I have found two ovarian cancer cell lines that secreted IL-6 and expressed both components of the IL-6 receptor signalling complex. When these cells were grown on plastic, CNTO328 had no effect on cell proliferation or survival. This suggested that IL-6 was not a growth factor for ovarian cancer cells in vitro. However, CNTO328 reduced constitutive secretion of IL-6, IL-1β, TNF-α, IL-8 and CCL2 by the ovarian cancer cells. The in vivo studies with human ovarian cancer xenograft models in nude mice showed that anti-IL-6 treatment had biological activity by inhibiting cell proliferation, macrophage infiltration and angiogenesis. In conclusion, the xenograft models and cell line experiments together with the clinical trial show that IL-6 may be a therapeutic target in ovarian cancer and exhibits both autocrine and paracrine actions within the ovarian cancer microenvironment

Paraneoplastic thrombocytosis in ovarian cancer

<p>Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.</p> <p>Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.</p> <p>Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.</p> <p>Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. </p&gt

Targeted therapeutic management of locally advanced, recurrent and metastatic cervical cancer

In the sphere of gynaecological malignancies, the chemotherapeutic management of advanced cervical cancer is exceptionally challenging. Significantly, the slow pace in the evolution of novel targeted therapies in treating this disease partly explains why it remains third only to breast and ovarian cancer in terms of female cancer mortality worldwide. Over the course of the past decade, only small increments in overall and progression-free survival using combination chemotherapy has been witnessed, with the doublet of platinum-agents plus paclitaxel becoming established as the optimal first-line regimen. However the median overall survival still remains desperately poor ranging between 9-18 months. With the recent explosion of adjunctive molecular targeted agents alongside chemotherapy, there has been significant scope for their inclusion into the treatment paradigms for locally advanced, recurrent and metastatic cervical cancer. Considerable impacts have been made by scrutinising the way in which signal transduction pathways can be modulated to improve survival in this setting. Specifically, bevacizumab and other agents targeting vascular endothelial growth factor (VEGF) have returned promising results, prompting a plethora of early-phase trials. Other areas of burgeoning interest include inhibition of epithelial growth factor receptor (EGFR), platelet-derived growth factor (PDGF), mammalian target of rapamycin (mTOR), histone deacetylase (HDAC),cyclooxygenase (COX), insulin growth factor receptor (IGFR) and activators of AMP kinase (AMPK). Currently, these areas represent exciting new frontiers in advanced cervical cancer management, having already proven a substantial benefit in other numerous tumour types. Though they are yet to make the leap from publication to clinical practice, targeted therapies undoubtedly point the way forward. This chapter aims to outline the current evidence to support their swift introduction in this grave disease, drawing on literature from in vitro and in vivo studies and also highlights the possible reasons for the paucity of clinical trials focused on the incorporation of agents that have shown efficacy in other gynaecological tumours

Chemotherapy advances in small-cell lung cancer

Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms

Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies

The platinum analogues, cisplatin and carboplatin, are among the most widely used chemotherapeutic agents in oncology. Both agents have a broad spectrum of clinical activity in numerous malignancies including gynaecological cancers, germ cell tumours, head and neck cancer, thoracic cancers and bladder cancer. Although the final mechanism of inducing tumour cell apoptosis is similar for both compounds, cisplatin has been shown to be more effective in treating specific tumour types. Whilst more favourable toxicity profiles are often associated with carboplatin, this can frequently translate to inferior response in certain malignancies. This review succinctly collates the evidence for the preferential use of these platinum analogues in particular settings in addition to the long-standing dilemma surrounding the paucity of biomarkers predicting response to these agents

Mucinous ovarian cancer: a therapeutic review

Mucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC). Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease. Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering ‘GI style’ chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations

A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients

Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC