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Class of 2016 Abstract / Objectives: To test whether ipilimumab therapy affects the endocrine system in patients with Metastatic Melanoma. Methods: A retrospective chart review was performed that included patients with Metastatic Melanoma that had at least one dose of ipilimumab. Results: The primary finding of this study is that 38% of patients used at least 20 mg of prednisone daily or more while on Ipilimumab therapy. Only 33% of patients had endocrine lab values reported. Conclusions: There was not enough data collected to adequately show that Ipilimumab affects the endocrine system. There was also insufficient reporting of appropriate serum levels. More research on the importance of reporting lab values while on ipilimumab therapy needs to be conducted.

Le mélanome cutané métastatique était un cancer au pronostic particulièrement péjoratif, jusqu’au développement récent de 2 classes pharmacologiques: l’immunothérapie, pour tous les mélanomes, et les thérapies ciblées, principalement pour les mélanomes porteurs de la mutation BRAF (50% des mélanomes cutanés). Mais l’apparition de résistance, et l’absence de thérapies ciblées sur les mélanomes non mutés BRAF, incitent à rechercher de nouvelles cibles thérapeutiques. Notre travail portait sur l’étude in vitro de la phosphodiestérase de type 4 (PDE4), une enzyme régulant la voie de l’AMPc, principale voie de différenciation mélanocytaire. L’objectif était d’évaluer le rôle de PDE4 dans le mélanome, et l’effet de son inhibition par des molécules pharmacologiques déjà disponibles sur le marché.Dans une première partie, nous avons étudié le rôle de PDE4 dans les cellules de mélanomes mutés sur BRAF. Nous avons montré que l’isoforme PDE4D5 est surexprimée dans le mélanome, et régule l’invasion cellulaire par un mécanisme faisant intervenir la focal adhesion kinase, FAK. Dans les tumeurs nous avons observé une association entre le niveau d’expression de PDE4D5 et le degré d’invasion du mélanome.Dans une seconde partie, nous avons étudié l’effet de l’inhibition de PDE4 sur la prolifération cellulaire. Nous avons montré que la croissance des cellules de mélanome muté BRAF cultivées sous forme de mélanosphères, enrichies en cellules initiatrices de tumeurs, est réduite en présence d’inhibiteurs de PDE4. De plus les lignées BRAF muté résistantes aux inhibiteurs de BRAF gardent une sensibilité aux inhibiteurs de PDE4. Ces résultats, et ceux de l’équipe établis dans le mélanome muté sur RAS, corroborent l’hypothèse que PDE4 pourrait être une cible thérapeutique d’intérêt dans le traitement du mélanome métastatique / Metastatic melanoma was associated with a pejorative prognosis, until the recent development of 2 pharmacological classes: immunotherapy for all types of melanomas and targeted therapies, mainly for melanomas carrying the BRAF mutation (50% of skin melanomas). However, the emergence of resistance, and the absence of targeted therapies to treat non-mutated BRAF melanomas, prompt further research to study new therapeutic targets.Our work focused on the in vitro study of phosphodiesterase type 4 (PDE4), an enzyme regulating the cAMP pathway, the main pathway controlling melanocyte differentiation. The objective was to evaluate the role of PDE4 in melanoma and the effect of its inhibition by already available pharmacological molecules.First, we studied the role of PDE4 in BRAF mutated melanoma cells. We found that the PDE4D5 isoform is overexpressed in melanoma cells, and regulates cell invasion through a mechanism involving a focal adhesion kinase (FAK). We observed in tumor samples an association between the level of expression of PDE4D5 and the degree of invasion by melanoma cells.Second, we studied the effect of PDE4 inhibition on cell proliferation. We found that the proliferation of BRAF mutated melanoma cells grown as melanospheres, enriched with tumor-initiating cells, is reduced in the presence of PDE4 inhibitors. In addition, mutated BRAF strains resistant to BRAF inhibitors remain sensitive to PDE4 inhibitors. These results corroborate the hypothesis that PDE4 could be a potential target in the treatment of metastatic melanoma

Distinction of primary skin adnexal carcinomas from cutaneous metastasis of adenocarcinomas is challenging. In this study, we evaluated podoplanin immunoreactivity in a series of primary skin adnexal tumors and adenocarcinomas metastatic to skin using a D2-40 antibody. The initial test series were composed of a total of 93 cases including 32 primary skin adnexal carcinomas, 46 benign primary adnexal tumors, and 15 cutaneous metastatic adenocarcinomas. We found that variable D2-40 reactivity was seen in all of the primary cutaneous carcinomas including sebaceous carcinomas (10/10), squamous cell carcinomas (10/10), porocarcinomas (4/4), trichilemmal carcinomas (4/4), skin adnexal carcinomas not otherwise specified (4/4), and in the majority of benign skin adnexal tumors. In contrast, no podoplanin immunoreactivity was seen in any of the 15 (0/15) cutaneous metastases. To confirm the initial findings and to further explore the utility of podoplanin reactivity in the distinction of these tumors, we also examined a test set of 35 unknown cases, including 21 adenocarcinomas metastatic to skin and 14 primary adnexal tumors, in a blinded fashion. In this test set of cases, podoplanin was negative in 22 cases and positive in 13 cases. Of the 22 podoplanin negative cases, 20 were proven to be metastatic adenocarcinoma. Of the 13 D2-40 positive cases, 12 were proven to be primary adnexal tumors. Our results suggest that podoplanin can be a useful tool to distinguish primary skin adnexal carcinomas form adenocarcinomas metastatic to skin with high sensitivity (94.5%) and specificity (97.2%).

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Thesis advisor: Pamela J. Grace / Purpose/Specific Aims: Van Manen’s hermeneutic phenomenological method was used to design this study aimed at better understanding the meaning of day-to-day living with advanced breast cancer in young women. Rationale/Significance of Study: There is a gap in knowledge about the particular needs and daily life experiences of this cohort. Very little data specifically addresses this population. The limited literature that exists suggests that, due to the particular stage of life, their needs differ from those at other life stages as well as those coping with earlier stages of breast cancer. These women have described themselves as being invisible and having to live with the knowledge that their future is uncertain. Thus, this qualitative study is an important initial step in expanding our understanding of what daily life is like for this population. Sample and Recruitment: Women aged 25–39 with Stage III or IV breast cancer were purposively recruited via private FacebookTM groups specifically for women with breast cancer. The final sample consisted of 12 participants from across the U.S. Incidentally, all were parents. Data Analysis: Data were collected through two or more semistructured interviews and written journals. Analysis followed van Manen’s method of immersion, reading, and rereading, and using manual coding and NVivo software to develop themes to capture the participants’ lifeworlds. Findings: The meaning of their experiences is captured by the overarching theme: Wearing the mask of wellness in the presence of life-threatening illness. Five major themes were identified: Wanting to be known as the person I am, I’m still Mom, Living is more than surviving, Getting through it, and Being connected to others. Conclusions: Findings highlight that these young women are managing multiple roles and responsibilities despite the ongoing challenges of treatment and symptom management. They feel that their needs and struggles are not well understood because to outsiders they do not look ill. This study provides a base for further research and eventually interventions. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

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Adoptive cell transfer techniques identify and isolate patient anti-tumor lymphocytes in vitro followed by ex vivo expansion of these tumor specific T cells. Identification and isolation of lymphocytes from patient tumors allows for the selection of anti-tumor lymphocytes that are highly specific for individual tumor antigens. Furthermore, recombinant technology allows for engineering of chimeric antigen receptors (CARs) which allow these T cells to target multiple tumor antigens. Techniques involving ex vivo growth lead to a 1,000- to 5,000-fold increase in numbers of lymphocytes. Cultured lymphocytes can then be infused via IV and growth maintained with administration of exogenous IL-2. Cancer patients are then monitored for both immunological activity as well as any adverse cytokine reactions. We looked at several trial studies for the application of adoptive cell transfer in metastatic melanoma compare the efficacy of the regimen to other established melanoma treatments. Adoptive transfer has proven to be effective for patients with late stage melanoma, however, the aim of this study was to examine some of the challenges in creating an effective standard protocol for adaptation in clinical settings, including difficulty in obtaining significant cell populations from tumors, challenges in the proliferation of these tumor-infiltrating lymphocytes (TIL) and determination of antigen-specificity, i.e. facilitation of a simplified and quicker approach to the therapy.

Le traitement du mélanome métastatique est longtemps resté cantonné à quelques chimiothérapies cytotoxiques à efficacité limitée. Récemment, le développement des immunothérapies et des thérapies ciblées a constitué une avancée majeure dans la prise en charge du mélanome. La découverte de mutations oncogéniques sur les voies de signalisation de la cellule tumorale a permis de définir de nouvelles cibles pour le développement d’ inhibiteurs pharmacologiques. Parmi ces mutations, la mutation BRAF V600E est présente dans 50% des mélanomes. Une des molécules anti-BRAF développée est le vémurafenib. L’efficacité de cette molécule a permis l’allongement de la durée de survie des patients en situation métastatique de 6 à 8 mois. Malheureusement, malgré la réponse initiale, l’échappement est la règle. Les mécanismes moléculaires responsables de la résistance acquise aux inhibiteurs de BRAF sont multiples et conduisent à l’activation de nombreuses voies de signalisation pour suppléer l’inhibition de BRAF. Actuellement la prise en charge des patients résistants aux inhibiteurs de BRAF n’est pas codifiée et s’avère complexe étant donné la multiplicité des mécanismes d’échappement. Dans le cadre de cette nouvelle approche de médecine personnalisée, de nouveaux outils doivent être développés dans le but (i) de tester l’efficacité de nouvelles molécules et (i) de tenter de prédire l’efficacité/la résistance des différents traitements disponibles. L’un de ces outils sont les xénogreffes de tumeurs issues directement des patients (Patient Derived Tumor Xenograft ou PDTX) ou « avatars ». Mon travail a consisté à mettre en place ce type d’outil pour répondre aux questions suivantes : Les modèles animaux développés sont-ils un bon modèle préclinique translationnel ? Permettent-ils d’étudier les modes d’action des nouvelles thérapies ciblées et d’explorer leurs mécanismes de résistance ? Si tel est le cas, peuvent-ils prédire une réponse clinique ? Différents modèles murins de xénogreffes de mélanome ont été mis au point et exploités. Des cellules tumorales puis des fragments de tumeurs ont été greffées en sous-cutané chez la souris immunodéficiente SCID. Les tumeurs ont été caractérisées en histologie et en biologie moléculaire pour montrer leur stabilité dans le modèle. Après plusieurs passages dans différentes générations de souris, les tumeurs conservent leurs mutations particulières. Par ailleurs différents traitements ont été administrés et la réponse à différentes stratégies thérapeutiques a été évaluée. Ce modèle nous a permis de valider l’efficacité des thérapies ciblées antiBRAF (vémurafenib) mais aussi d’autres approches visant les particularités métaboliques du mélanome. Le modèle avatar a permis de tester in vivo une association thérapeutique innovante qui associe un accélérateur de la phosphorylation mitochondriale, le DCA, et une molécule pro-oxydante, l’elesclomol, confirmant l’effet synergique obtenu in vitro. Par ailleurs l’elesclomol a pu être testé in vivo sur une tumeur devenue résistante à l’inhibiteur de BRAF, le vemurafenib. En outre, le modèle avatar constitue un bon modèle préclinique permettant d’aider directement le clinicien dans ses choix thérapeutiques. En effet nous avons réalisé une PDTX tout au long de l’évolution métastatique d’une patiente. Cette PDTX a permis de tester l’efficacité du vemurafenib et de réintroduire ce traitement à la patiente qui a pu bénéficier d’une amélioration clinique notable. 7 autres PDTX de patients ont été développées permettant de renforcer le modèle et de suivre de manière personnalisée le traitement de ces patients.Grâce à ce travail, nous définissons la place que peuvent prendre les avatars dans la prise en charge actuelle du mélanome métastatique. Ces modèles donnent une réponse précoce quant à leur résistance et aux alternatives thérapeutiques de seconde ligne. / For a long time the standard treatment for metastatic melanoma has been confined to a few cytotoxic chemotherapies with limited efficacy. Recently, the development of immunotherapies and targeted therapies represents major headways in melanoma care management. The discovery of oncogenic mutations on the signaling pathways of the tumor cell allowed the definition of new targets for developing inhibitor drugs. Among these mutations, BRAF V600E is seen in 50% of all melanomas. Vemurafenib is one of the anti-BRAF molecules recently developed. It has shown its efficacy with metastatic patients showing a survival increased by 6 to 8 months. Unfortunately, in spite of the initial positive reaction, the development of a resistance mechanism is ineluctable. There are numerous molecular mechanisms responsible for the acquired resistance to BRAF inhibitors which activate numerous signaling pathways to make up for the BRAF inhibition. Today, there are no standards of care for patients who become resistant to BRAF inhibitors. In the framework of this new personalized care approach, new tools must be developed to (i) test the efficacy of new molecules and (ii) try to predict the efficacy/resistance of the various treatments available. One of these tools is the Patient Derived Tumor Xenograft or PDTX, i.e. xenografts from tumors directly harvested on patients.My work consisted in implementing this type of tool to try and bring an answer to the following questions: Are the developed animal models a good tool for preclinical cross-sectional studies? Can they help study the action modes of new targeted therapies and explore their resistance mechanisms? If this is the case, can they predict a clinical response? Various murine models of melanoma xenografts have been designed and used. Tumor cells and later on tumor fragments were grafted subcutaneously in immunosuppressed SCID mice. Tumors were characterized in histology and molecular biology to show the stability of the model. After several passages in various generations of mice, the tumors retain their specific mutations. Furthermore, various treatments have been administered and the answers to the various therapeutic strategies have been evaluated. This model allowed us to validate the efficacy of antiBRAF targeted therapies (vemurafenib) but also other approaches targeting the metabolic characteristics of melanoma. This avatar model enabled to test in vivo an innovating therapeutic combination, associating an accelerator of oxidative phosphorylation, DCA, to a pre-oxidative molecule, elesclomol, validating the synergic effect obtained in vitro. Furthermore, elesclomol was tested in vivo on a tumor which became resistant to BRAF, vemurafenib. Furthermore, PTDX is a good preclinical tool to guide clinicians in their therapeutic choices. In fact we were able to develop a PDTX during the entire metastatic progression of a patient. This PDTX enabled us to test the efficacy of vemurafenib and reintroduce the treatment to the patient, who showed noticeable clinical improvements. Seven other PDTX were developed in order to reinforce the model and follow, in a personalized manner, the treatment of these seven patients. Thanks to this work, we are able to define the role of avatars in the care management of metastatic melanoma. These models give an early answer regarding tumor resistance and alternative second-line therapies.