Breast cancer has changed in recent years from a terminal condition to a chronic disease, which can significantly impact a couple's relationship and overall adjustment. The first objective was to survey the shared and reciprocally determined adjustment processes which unfold within couples who face breast cancer. Attachment theory was then used as the grounding framework to both understand interpersonal dynamics and to provide a rationale for offering empirically-supported Emotionally Focused Therapy (EFT) to couples experiencing unremitting psychological and relational distress following diagnosis and treatment for breast cancer. The second objective involved evaluating the clinical efficacy of EFT on couples' psychological adjustment and patients' Natural Killer Cell Cytotoxicity (NKCC)---an important immune parameter implicated in control of metastatic disease. Twelve couples were randomized to receive either twenty sessions of EFT or Psycho-education (PE). A multiple baseline experimental design across couples was used. Results indicated that, compared to couples randomized to PE, those who received EFT evidenced more variation on outcome variables following EFT. Specifically, more than 50% of couples who received EFT evidenced clinically significant improvement in dyadic adjustment, and quality of life, as well as attenuation in mood disturbance and trauma symptoms. Women randomized to EFT evidenced more variation in response to treatment, with half of the sample experiencing small, but clinically irrelevant up regulation, in NKCC, while the other half showed clinically significant down-regulation in NKCC. Women receiving PE showed no changes in NKCC. More importantly, shifts in NKCC were in keeping with trajectories in dyadic adjustment and clinical events unfolding during the course of treatment. Findings provided initial support for offering EFT to couples experiencing emotional and relational following diagnosis and treatment of early breast cancer. Changes observed in NKCC, though in keeping with established relationships with psychological distress, were more tentative in nature.

Viral treatment of cancer has been described since the beginning of the twentieth century. With the increasing need for effective targeted cancer therapies, the oncolytic virus platform has been revisited. Clinical trials have demonstrated that oncolytic viruses are well tolerated, but their ability to eliminate tumor burden or effectuate cures is poor. This thesis attempts to address enhancing the oncolytic virus efficacy. The strategy is to modulate characteristics of the rhabdovirus by adding or swapping envelope genes of interest in order to enhance oncolytic activity, specifically by addressing tumor spread, immune evasion and safety. The fusogenic protein from reovirus is used to generate a recombinant VSV to enhance viral spread within the tumor. Similarly, recombinant VSVs are generated with envelope proteins either from other vesiculovirus members or from a beta-retrovirus, and used to demonstrate tumor infectivity in the presence of neutralizing antibodies. The recombinant VSV expressing the beta-retrovirus envelope protein demonstrates altered viral tropism, and like the replication incompetent VSV/FAST recombinant is not neurotoxic in animal models.

Human ovarian cancer is the most lethal gynecological malignancy. Although cisplatin (CDDP) and paclitaxel are the first-line chemotherapeutic agents for ovarian cancer, chemoresistance is a major therapeutic problem with mechanisms involved still not well understood. Dysregulation of the apoptotic cascade may be a causative factor for chemoresistance. Indeed gene products involved in the regulation of apoptosis, including the PI3K/Akt and Flice-Like Inhibitory Protein (FLIP) are frequently over-expressed and/or dysregulated in chemoresistant cells. FLIP, a caspase-8 analogue, modulates death receptor-mediated apoptosis by preventing caspase-8 activation. Since FLIP may have a critical involvement in ovarian cancer chemoresistance, it is importance to understand its role, the molecular and cellular mechanisms by which FLIP is regulated, and if and how dysregulated FLIP degradation is involved in the etiology of chemoresistance. Human ovarian cancer cell lines were used to establish the possible involvement of FLIP in the regulation of CDDP sensitivity in vitro and to assess the mechanism by which CDDP regulates FLIP. We demonstrated that CDDP down-regulates FLIP content, induces caspase-8 and -3 activation and apoptosis in chemosensitive ovarian cancer cells, but not in their resistant counterparts. Moreover, we observed that FLIP over-expression in chemosensitive cells attenuates CDDP sensitivity, while FLIP down-regulation sensitizes chemoresistant cells to CDDP. We further demonstrated that CDDP had no effects on FLIP mRNA abundance but down-regulated FLIP protein content in chemosensitive cells, a response attenuated by proteasome inhibitors. Itch is an E3 ligase protein involved in protein ubiquitination. CDDP also enhances FLIP-p53-Itch cell membrane co-localization, and FLIP ubiquitination in chemosensitive but not resistance cells. In addition, Itch silencing attenuates CDDP-induced FLIP ubiquitination. p53 siRNA also attenuates FLIP-Itch and FLIP-p53 interactions and FLIP ubiquitination. While Akt activation inhibits CDDP-induced FLIP degradation and apoptosis in chemosensitive cells, these responses are facilitated by dominant-negative Akt expression in their resistant variants. Finally, p53 siRNA attenuates CDDP-induced and dominant negative (DN)-Akt-facilitated FLIP-p53 binding and FLIP ubiquitination in resistant cells. These studies improve our understanding of FLIP involvement in chemoresistance, the mechanism by which CDDP regulates FLIP, and dysregulation of FLIP degradation in chemoresistance in ovarian cancer.

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