Faculty Bibliography

Treatment with tumour necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is seen emerging between TNF antagonists and development of squamous cell carcinomas (SCCs) of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus infection). We present here a case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to our service after several months of increasing left pelvis and buttock pain. Evaluation with a computerised tomography (CT)-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a fluorodeoxyglucose (FDG) positron-emission tomography (PET) an additional area of uptake was identified in the left posterior rectum corresponding to a 1 cm nodule palpable on digital exam. Colonoscopic biopsy revealed a basaloid SCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have given arise to this unrestrained neoplastic growth. It thereby underscores the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage.

Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of alpha-smooth muscle actin-expressing stromal cells. Integrin alpha10beta1 can serve as a receptor for the HU177 epitope in alpha-smooth muscle actin-expressing stromal cells and subsequently regulates Erk-dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized alpha10beta1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors.

Occult endometrial cancer is occasionally discovered in women with Lynch syndrome undergoing risk-reducing hysterectomy. The case presented here demonstrates that preoperative endometrial sampling can help detect these occult cancers; however, there are currently no recommendations for this preoperative intervention. A 50-year-old woman with Lynch syndrome underwent endometrial sampling prior to planned risk-reducing hysterectomy and bilateral salpingo-oophorectomy. The endometrial biopsy demonstrated a serous endometrial cancer. The patient was counselled regarding the diagnosis and revised operative plan, which now included staging, prior to surgery. Although the prevalence of occult endometrial cancer at the time of risk-reducing surgery in women with Lynch syndrome remains unknown, preoperative endometrial sampling may allow for improved patient counselling and surgical planning in this population, and can help avoid a subsequent surgery for staging.

Advanced ovarian cancer carries a grim prognosis and development of targeted therapies to improve outcomes has become an active area of research in this disease. The epidermal growth factor receptor (EGFR) and HER2/neu have shown to be overexpressed in ovarian cancer and there have been several clinical trials evaluating anti-EGFR and HER2 therapies in ovarian cancer. Unfortunately, the drugs have shown minimal efficacy and more recent work has now focused on identifying mechanisms of resistance and alternative ways of targeting these pathways. This review will discuss the currently published trials with anti-EGFR and HER2 agents in ovarian cancer and the further directions of study with these pathways.

In ovarian cancer, multiple attempts to adjust the standard taxane/platinum doublet by adding cytotoxic therapy or varying scheduling, dosage, and delivery have been met with limited success. Alternative methods to improve the grim prognosis of ovarian cancer, including molecular therapies, are currently under investigation. Efforts have been made to study tyrosine kinase inhibitors (including imatinib and pazopanib), Src kinase inhibitors and histone deacetylase inhibitors (HDACi) in combination with taxanes/platinums in order to improve efficacy. Unfortunately, while many pre-clinical and early phase clinical trials argue that the utilization of these molecular targets may enhance survival, only modest benefit has been seen in larger clinical trials. Other agents that have been evaluated include proteasome inhibitors, folate receptor antagonists, MEK inhibitors and opiate antagonists. In this review, we discuss the mechanisms of these targeted therapies and highlight the current and ongoing clinical trials that utilize these targeted agents in combination with taxanes and platinums in advanced ovarian cancer.

In the last 50 years the oncology has experienced remarkable changes resulting in transforming malignant germ-cell testicular tumors from highly fatal to nearly uniformly cured neoplasms. This clinical landmark was justly attributed to the identification of cisplatin by Barnett Rosenberg in his experiments dating to 1965. On this 50th anniversary of this discovery, one is reminded of the following key aspects in cancer therapeutics: 1) the life-story of Barnett Rosenberg and his legacy that included organizing nearly quadrennial "platinum" meetings incorporating advances in cancer biology into evolving therapeutic strategies; 2) the search for less toxic analogs of cisplatin leading to the development of carboplatin; 3) clinical research into attenuation of cisplatin toxicities; 4) oxaliplatin and the expansion of the therapeutic spectrum of platinum compounds; and 5) the ongoing multifaceted investigations into the problem of "platinum resistance".