Jermaine Coward

IL6-STAT3-HIF Signaling and Therapeutic Response to the Angiogenesis Inhibitor Sunitinib in Ovarian Clear Cell Cancer

Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA. Experimental Design: Gene expression and DNA copy number were carried out using primary human OCCA tumor samples, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography. Results: We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe amplification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer. Conclusions: Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer. Clin Cancer Res; 17(8); 2538–48. ©2011 AACR.

Interleukin-6: An angiogenic target in solid tumours

During the past decade, incorporating anti-angiogenic agents into the therapeutic management of a myriad of malignancies has in certain cases made a significant impact on survival. However, the development of resistance to these drugs is inevitable and swift disease progression on their cessation often ensues. Hence, there is a drive to devise strategies that aim to enhance response to anti-angiogenic therapies by combining them with other targeted agents that facilitate evasion from resistance. The pleiotropic cytokine, interleukin-6 (IL-6), exerts pro-angiogenic effects in the tumour microenvironment of several solid malignancies and there is emerging evidence that reveals significant relationships between IL-6 signalling and treatment failure with antibodies directed against vascular endothelial growth factor (VEGF). This review summarises the role of IL-6 in pivotal angiogenic processes and preclinical/clinical research to support the future introduction of anti-IL-6 therapies to be utilised either in combination with other anti-angiogenic drugs or as a salvage therapy for patients with diseases that become refractory to these approaches.

New perspectives on targeted therapy in ovarian cancer

Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose) inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer.

Size Does Matter: Why Polyploid Tumor Cells are Critical Drug Targets in the War on Cancer.

Tumor evolution presents a formidable obstacle that currently prevents the development of truly curative treatments for cancer. In this perspective, we advocate for the hypothesis that tumor cells with significantly elevated genomic content (polyploid tumor cells) facilitate rapid tumor evolution and the acquisition of therapy resistance in multiple incurable cancers. We appeal to studies conducted in yeast, cancer models, and cancer patients, which all converge on the hypothesis that polyploidy enables large phenotypic leaps, providing access to many different therapy-resistant phenotypes. We develop a flow-cytometry based method for quantifying the prevalence of polyploid tumor cells, and show the frequency of these cells in patient tumors may be higher than is generally appreciated. We then present recent studies identifying promising new therapeutic strategies that could be used to specifically target polyploid tumor cells in cancer patients. We argue that these therapeutic approaches should be incorporated into new treatment strategies aimed at blocking tumor evolution by killing the highly evolvable, therapy-resistant polyploid cell subpopulations, thus helping to maintain patient tumors in a drug sensitive state.

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.

Serum HE4 as a prognostic marker in endometrial cancer — A population based study

OBJECTIVE HE4 has emerged as a promising biomarker in gynaecological oncology. The purpose of this study was to evaluate serum HE4 as a biomarker for high-risk phenotypes in a population-based endometrial cancer cohort. METHODS Peri-operative serum HE4 and CA125 were measured in 373 patients identified from the prospective Australian National Endometrial Cancer Study (ANECS). HE4 and CA125 were quantified on the ARCHITECT instrument in a clinically accredited laboratory. Receiver operator curves (ROC), Spearman rank correlation coefficient, and chi-squared and Mann-Whitney tests were used for statistical analysis. Survival analysis was performed using Kaplan-Meier and Cox multivariate regression analyses. RESULTS Median CA125 and HE4 levels were higher in stage III and IV tumours (p<0.001) and in tumours with outer-half myometrial invasion (p<0.001). ROC analysis demonstrated that HE4 (area under the curve (AUC)=0.76) was a better predictor of outer-half myometrial invasion than CA125 (AUC=0.65), particularly in patients with low-grade endometrioid tumours (AUC 0.77 vs 0.64 for CA125). Cox multivariate analysis demonstrated that elevated HE4 was an independent predictor of recurrence-free survival (HR=2.40, 95% CI 1.19-4.83, p=0.014) after adjusting for stage and grade of disease, particularly in the endometrioid subtype (HR=2.86, 95% CI 1.25-6.51, p=0.012). CONCLUSION These findings demonstrate the utility of serum HE4 as a prognostic biomarker in endometrial cancer in a large, population-based study. In particular they highlight the utility of HE4 for pre-operative risk stratification to identify high-risk patients within low-grade endometrioid endometrial cancer patients who might benefit from lymphadenectomy.

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.

PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer

Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.

Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors

The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2-12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon.

The role of interleukin-6 in gynaecological malignancies

There are many parallels between gynaecological cancers in relation to cytokine networks within their respective tumour microenvironments and evidence to support interleukin-6 (IL-6) being an appropriate therapeutic target in these diseases. This article provides an overview on IL-6 biology including updates on novel discoveries in IL-6 signalling and then focuses on the role of IL-6 in processes such as cell proliferation, migration, angiogenesis, evasion of tumour immunity and chemoresistance and presents data relating to the abrogation of these processes with anti-IL-6 targeted therapy in preclinical and clinical studies. The overall aim will be to highlight the necessity for further translational studies concentrating on combinations of anti-IL-6/IL-6R therapies with other novel targets in an attempt to significantly improve overall survival in patients with gynaecological cancers.