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Investigational Chemotherapy and Novel Pharmacokinetics for the Treatment of Cancers of the CNS

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Investigational Chemotherapy and Novel Pharmacokinetics for the Treatment of Cancers of the CNS Graduate Theses, Dissertations, and Problem Reports 2018 Investigational Chemotherapy and Novel Pharmacokinetics for the Treatment of Cancers of the CNS Neal Shah Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Shah, Neal, "Investigational Chemotherapy and Novel Pharmacokinetics for the Treatment of Cancers of the CNS" (2018). Graduate Theses, Dissertations, and Problem Reports. 7250. https://researchrepository.wvu.edu/etd/7250 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Investigational Chemotherapy and Novel Pharmacokinetics for the Treatment of Cancers of the CNS Neal Shah, Pharm.D. Dissertation submitted to the School of Pharmacy at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical and Pharmacological Sciences Paul R. Lockman, Ph.D., Chair Erik A. Bey, Ph.D., Christopher P. Cifarelli, M.D., Ph.D., Lori A. Hazlehurst, Ph.D., William Petros, Pharm.D. Department of Pharmaceutical and Pharmacological Sciences Robert C. Byrd Health Sciences Center Morgantown, West Virginia 2018 Keywords: Brain metastases, breast cancer, lung cancer, blood-tumor barrier, chemotherapy Copyright 2018 Neal Shah ABSTRACT Investigational Chemotherapy and Novel Pharmacokinetics for the Treatment of Cancers of the CNS Neal Shah, Pharm.D. This dissertation (a) detailed the optimal imaging times and quantifiable intervals of the non-toxic tumor surrogate marker D-luciferin in metastatic and primary brain tumors, (b) characterized the creation, passive permeability, efflux pump status, and vascularity of a widely-used EGFR-mutant lung cancer cell line, (c) evaluated the in-vitro cytotoxicity and in-vivo efficacy of three novel chemotherapeutic agents on brain metastases of lung and breast cancer as well as primary glioblastoma, and (d) provided a review of the current clinical and preclinical treatment options for breast cancer and lung cancer brain metastases, and primary glioblastoma. ACKNOWLEDGEMENTS The work presented in this dissertation would have been unachievable without collective and collaborative effort. I am eternally grateful for all the help I have received through the years. First, I would like to profoundly thank my mentor Dr. Paul Lockman. Without your guidance through these three years I would be completely lost. Your support has meant the world to me, from my initial uneasiness in the first year to surprising you in your office and saying I wanted to publish papers and graduate in five months. I have learned so much from you, not only in the field of science, but life in general. You remain creative in scientific approach and data publication, which is something I am slowly starting to incorporate into my life. Your flexibility of balancing research and life has allowed me to explore life and pursue the field of medicine I wish to practice. I feel a connectedness as our backgrounds are both in clinical practice and this allows us to balance the mindset of clinician scientists. I enjoyed all of our time together and I hope to collaborate with you in the future. Thank you, Dr. Julie Lockman, for working with me through the hectic race at the end for my Masters. You both have shown me the virtues of patience, hard work, determination, and how an ideal partnership works. I would also like to thank all the members in my committee for their assistance throughout the time spent in my PhD. Dr. Cifarelli, Dr. Hazlehurst, Dr. Petros and Dr. Bey, you reviewed my grant application, provided letters of support and recommendation, gave me recommendations for experimental approach and creative suggestions to make my work more impactful. You have seen my progress throughout graduate school and I hope I have adequately evolved as a scientist in your eyes. iii To my seniors, the postdoctoral scholars: Dr. Chris Adkins, where to begin? We bonded over Indian Pale Ales and Game of Thrones, hot sauce, exercise, and transitioned from being labmates to friends. One of the most important things I learned from you is how to be critical of scientific work, especially your own. Thank you for all of your patience during the transition of my first year, and congratulations again on your position as a pharmacy school professor. If I move away from Morgantown, I will be sure to eat some Peppebronis in your honor. Dr. Raj Jagannathan, you had a simple motto: “make science easy”. Thank you both so much. To my fellow Lockman Lab PhD graduates: It has been a journey, hasn’t it? Dr. Tori Terrell-Hall, though our time was limited, it was fantastic. I enjoyed seeing you problem solve and balance your children and lab work. If I am ever in Texas, I will definitely contact you! Besides, I think I owe you quite a bit of money from the swear jar. Dr. Afroz Mohammad, there are no shortage of fond memories with you. Besides Dr. Lockman, I have spent the most time in lab with you, and you have changed many life views I held. You stayed very late, long beyond your own long days to help me out with perform essential procedures creating figures. Even after you defended your dissertation, up until the day you left, you helped me out. Your upbeat and constantly positive attitude has shown me there is utility in being optimistic. We laugh more than I thought was possible. There are so many, most likely too many amazing conversations and quotes: your “vegan” diet, going to a bar and ordering shots of water, coats-quotes, me being “hot” from radiation…. you remain an essential part of the Lockman Lab, and we will stay in contact! To the future doctors: Rachel Tallman, I owe much of this dissertation to you. Without your countless hours of slicing brains and initial imaging, much of this work would have taken another full year. We have had some great times together, from iv working out and running to bar-hopping and that one time, hammocking. I am so proud of you for getting into medical school and I promise I will continue to yell at you when I see you in the hospital. Memorable quote: “There’s no ‘a’ in orange! Except in the middle…” Dr. Katie Jarrell, I genuinely think you have made me better, nicer, and more human. It is always great to hang out with you, discuss life or movies or Game of Thrones, your future and pharmacy career plans, and so much more. You created “Neal on Wheels”! I am looking forward to all of our graduations and seeing where we all go throughout life. You both have helped me out so much! To the current Lockman Lab PhD students: Samuel Sprowls, thank you for making me push myself harder in all aspects of life, especially exercise. I will never forget the day you helped me move and figure out how apartment addresses work. You and Chris may be the only people who like Game of Thrones more than I do. Your most memorable quote for when I hit a new lifting record: “Me: Guess what I got on inner leg? Sam: Herpes?” Mark Pinti, thank you for staying all those long hours in the IVIS and helping me out with imaging and weighing. Pushkar Saralkar, thank you for all your assistance with IC50s and experimental analysis, as well as showing me how to play tennis. I look forward to seeing how massive the Plastic Throne will be. Schuyler Vickers, it will be great to see where your projects go, and what types of meat you “have your way with”. Without the assistance provided by you four, this dissertation would be incomplete. To the former undergraduates, who are now pursuing a PhD: Emma Dolan, I am not surprised you ended up with acceptances at Scripps and Duke! It was great catching up with you in DC for AACR. Jessie Griffith, your most memorable quote is undoubtedly “How many doctorates does it take to move a cart?” The world may never know this answer, though I have confirmed it is not three. I hope you are staying warm in v Minnesota. Thank you both for all the memories and for help in the initial years of my PhD. To the imaging facility, employees of OLAR, and members of the Pugacheva, Gibson, and Hazlehurst labs: Thank you for all the patience and assistance with these massive projects. It was frustrating and time-consuming to juggle the hundreds of animals we did in such a short time span, but you helped me get data I needed. To Dr. Szklarz, Dr. Salati, Dr. Siderovski, and Dr. Geldenhuys: Thank you for always being in my corner and being flexible. Even when my ambition surpassed a passable possibility, you believed in me and helped me make this fervor into reality. I hope I have made you proud! To Dr. Kolodney, thank you for showing me how a real MD/PhD scientist is supposed to be. I focus more on clinical aspects, but you reminded me that a clinician scientist always keeps basic science in the back of their mind.
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