Rebecca Phaeton

Issues in cervical cancer incidence and treatment in Hiv

Purpose of review Cervical disease burden continues to be especially high in HIV-infected women, even in the era of effective antiretroviral medications. This review discusses the multiple issues surrounding HIV-associated cervical cancer. Also, the unique treatment-related issues in HIV-associated cervical cancer are addressed. Recent findings The incidence of invasive cervical cancer has remained stable in industrialized nations; however, it is only estimated in developing countries secondary to a relative lack of data collection and registries. Trends in HIV-associated cervical cancer have changed in the highly active antiretroviral therapy (HAART) era. Recent molecular pathways suggest that the natural progression of human papillomavirus infection, the causal agent in all cervical cancers, may be related to immune system dysfunction as well as HIV/human papillomavirus synergistic mechanisms. When highly active retroviral therapies are used, invasive cervical cancer treatments are impacted by concomitant drug toxicities that could potentially limit therapeutic benefit of either HAART or the standard of care treatment for locally advanced cervical cancer, concomitant chemoradiotherapy. Summary The significance and care of the patient with invasive cervical cancer is becoming a geographically relevant phenomenon such that it may be time to re-address the global definition. Further studies in treatment issues and drug–drug interactions with cervical cancer treatments in the setting of HIV are paramount.

The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice†

Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95% of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors.

Combined treatment of the experimental human papilloma virus-16-positive cervical and head and neck cancers with cisplatin and radioimmunotherapy targeting viral E6 oncoprotein

Background:Human papilloma virus (HPV) is implicated in >99% of cervical cancers and ∼40% of head and neck squamous cell carcinoma (HNSCC). We previously targeted E6 oncogene with 188Rhenium-labelled monoclonal antibody (mAb) C1P5 to HPV16 E6 in cervical cancer and HNSCC. Intranuclear E6 can be accessed by mAbs in non-viable cells with leaky membranes. As radioimmunotherapy (RIT) efficacy depends on the availability of target protein—we hypothesised that pretreatment with cisplatin will kill some tumour cells and increase E6 availability for RIT.Methods:Mice with subcutaneous HPV16+ cervical (CasKi) and HNSCC (2A3) tumours were pretreated with 0–7.5 mg kg−1 per day cisplatin for 3 days followed by 188Re-C1P5 and biodistribution was performed 24 h later. For RIT, the animals were treated with: 5 mg kg−1 per day cisplatin for 3 days; or 5 mg kg−1 per day cisplatin for 3 days followed 200 or 400μCi 188Re-C1P5 mAb; or 200 or 400μCi 188Re-C1P5 mAb; or left untreated, and observed for tumour growth for 24 days.Results:Pretreatment with cisplatin increased the uptake of 188Re-C1P5 in the tumours 2.5 to 3.5-fold and caused significant retardation in tumour growth for CasKi and 2A3 tumours in both RIT alone and cisplatin, and RIT groups in comparison with the untreated control and cisplatin alone groups (P<0.05). The combined treatment was more effective than either modality alone (P<0.05).Conclusion:Our study demonstrates that preceding RIT targeting E6 oncogene with chemotherapy is effective in suppressing tumour growth in mouse models of HPV16+ cancers.

Insights into the Dichotomous Regulation of SOD2 in Cancer

While loss of antioxidant expression and the resultant oxidant-dependent damage to cellular macromolecules is key to tumorigenesis, it has become evident that effective oxidant scavenging is conversely necessary for successful metastatic spread. This dichotomous role of antioxidant enzymes in cancer highlights their context-dependent regulation during different stages of tumor development. A prominent example of an antioxidant enzyme with such a dichotomous role and regulation is the mitochondria-localized manganese superoxide dismutase SOD2 (MnSOD). SOD2 has both tumor suppressive and promoting functions, which are primarily related to its role as a mitochondrial superoxide scavenger and H2O2 regulator. However, unlike true tumor suppressor- or onco-genes, the SOD2 gene is not frequently lost, or rarely mutated or amplified in cancer. This allows SOD2 to be either repressed or activated contingent on context-dependent stimuli, leading to its dichotomous function in cancer. Here, we describe some of the mechanisms that underlie SOD2 regulation in tumor cells. While much is known about the transcriptional regulation of the SOD2 gene, including downregulation by epigenetics and activation by stress response transcription factors, further research is required to understand the post-translational modifications that regulate SOD2 activity in cancer cells. Moreover, future work examining the spatio-temporal nature of SOD2 regulation in the context of changing tumor microenvironments is necessary to allows us to better design oxidant- or antioxidant-based therapeutic strategies that target the adaptable antioxidant repertoire of tumor cells.

Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer

Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV‐positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy—we performed RIT of experimental cervical cancer with Rhenium‐188 (188Re) and Lutetium‐177 (177Lu)‐labeled mAb C1P5 to E6. The biodistribution of 188Re‐ and 177Lu‐labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either 188Re‐C1P5 or 177Lu‐C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of 188Re‐ and 177Lu‐C1P5 mAbs‐induced double‐strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti‐gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both 177Lu‐C1P5 and 188Re‐C1P5. The dose to the liver was five times higher for 177Lu‐C1P5. The doses to the tumor were 259 and 181 cGy for 177Lu‐C1P5 and 188Re‐C1P5, respectively. RIT with either 177Lu‐C1P5 or 188Re‐C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in 177Lu‐C1P5 group only and on day 10 it was observed in both 177Lu‐C1P5 and 188Re‐C1P5 groups. 188Re‐ and 177Lu‐labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer.

Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer

BACKGROUND In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. MATERIALS & METHODS We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific (188)Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. RESULTS The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. CONCLUSION We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy.

The role of pemetrexed in recurrent epithelial ovarian cancer: A scoping review

Ovarian cancer is the leading cause of mortality among gynecologic malignancies, with most cases diagnosed at an advanced stage. Despite an initial response, most develop a recurrence and subsequent resistance to standard therapies. Pemetrexed (AlimtaTM) is a new generation multi-targeted antifolate initially approved for the treatment of malignant pleural mesothelioma. In recent years, it has shown promise in the treatment of recurrent epithelial ovarian cancer. In this review, we outline the current literature and discuss the future of pemetrexed in the setting of recurrent epithelial ovarian cancer.

Large cell neuroendocrine carcinoma (LCNEC) of the ovary: A case report and review of the literature

Neuroendocrine tumors consist of a spectrum of malignancies that arise from the neuroendocrine cell system. This group of tumors can be divided into well-differentiated (i.e. carcinoid) and poorly differentiated neuroendocrine neoplasms (i.e. small cell and large cell) [1]. Neuroendocrine carcinomas of the female genital tract are uncommon. More specifically, large cell neuroendocrine carcinoma (LCNEC) of the ovary is an exceedingly rare diagnosis. These malignant tumors are associated with an aggressive clinical course with a short survival, even when diagnosed at an early stage. The majority of LCNECs of the ovary are associated with surface epithelial ovarian tumors. We have identified 37 documented cases in the literature. Eight cases of primary LCNEC of the ovary have been described without any concomitant epithelial ovarian component [1,2]. In this report, we present a case of a primary LCNEC of the ovary without an epithelial component with a relatively prolonged survival. Additionally, we summarize the current literature regarding the management of this rare tumor.