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Principal Investigator: Lissah Kyalamboka Johnson
Organization: HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
Fiscal Year: 2024
Award: $44,720
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Death rates have decreased across many cancer types owing to improved early detection and treatment
methods, but remained largely stagnant for ovarian cancer over the last four decades. High grade serous
ovarian carcinoma (HGSOC) is the most common and deadly subtype, accounting for almost 70% of all
ovarian cancer cases and 70-80% of deaths. HGSOC likely develops from secretory cells of the fallopian tube
epithelium (FTE) and neoplastic transformation typically produces highly metastatic tumor cells that are p53
mutant and homologous recombination defective. Apoptosis (programmed cell death) is a fundamentally
important process for removing damaged and malignant cells and evasion of apoptosis is a hallmark of cancer.
The intrinsic apoptosis pathway is controlled by the BCL-2 family of proteins, which are often dysregulated in
cancer cells to confer a survival advantage. We have recently detected an upregulation of the BCL2L1 gene,
which encodes pro-survival protein BCL-XL, in HGSOC compared to normal fallopian tube epithelium. This
upregulation produces a dependency on this pro-survival protein that may be targeted therapeutically. For my
F31 research proposal, I hypothesize that HGSOC cells have increased pro-survival protein expression,
particularly BCL-XL, to buffer against the increased pro-apoptotic signaling that is associated with neoplastic
transformation, which can be therapeutically targeted to increase tumor cell death. I propose to test this in
three aims: 1) ascertain apoptotic regulation and pro-survival protein dependence in pre-malignant and
malignant stages of transformation; 2) use HGSOC patient derived xenograft (PDX) mouse models to assess
the efficacy of combining pro-survival protein targeting drugs with first-line chemotherapeutics to enhance
tumor cell death; and 3) elucidate how hormone and follicular fluid exposure affects apoptotic regulation in
fallopian tube epithelial cells in an air-liquid interface culture. The training plan for this proposal is designed to
give me the mentorship, experience and skillset needed to obtain a postdoctoral position and ultimately
transition into an independent research career working in the field of gynecological cancer biology. Being
mentored by my sponsors, Drs. Kristopher Sarosiek and David Christiani, and working with close collaborators
that specialize in ovarian cancer research will allow me to learn the necessary laboratory techniques and gain
subject matter expertise in apoptosis, ovarian carcinogenesis, cancer therapeutics and environmental health
as it relates to cancer risk. The Science Advisory and Career Mentoring committees that I have established will
provide further guidance in my growth as a successful, independent scientist. I will publish manuscripts and
attend conferences to present my findings and hone my written and verbal scientific communication.
Ultimately, this F31 will provide me with the training and expertise necessary for a career in cancer research
and potentially an opportunity to positively impact the lives of women diagnosed with ovarian cancer.
Terms: <Accounting><Affect><Air><Antioncogene Protein p53><Anzatax><Apoptosis><Apoptosis Pathway><Apoptotic><Asotax><Autoregulation><B-Cell CLL/lymphoma 2><B-Cell Chronic Lymphocytic Leukemia Associated Oncogene><B-cell Leukemia 1><B-cell lymphoma protein 2><B-cell lymphoma-extra large><BCL><BCL-2 Protein><BCL-XL><BCL1 Oncogene><BCL2 protein><BCL2-Like 1><BCL2-Related Gene><BCL2-Related Protein, Long Isoform><BCL2-Related Protein, Short Isoform><BCL2L1><BCL2L1 gene><BCLX><BCLXL><BCLXS><Bcl-XL protein><Body Tissues><Bristaxol><Buffers><CBDCA><Cancer Biology><Cancer Induction><Cancers><Carboplatin><Carboplatino><Carcinoma Cell><Cell Body><Cell Communication and Signaling><Cell Death><Cell Line><Cell Signaling><Cell Survival><Cell Viability><CellLine><Cells><Cellular Transformation><Cellular Tumor Antigen P53><Cessation of life><Chemoresistance><Communication><Corpus Luteum Hormone><Data><Death><Death Rate><Delta4-pregnene-3,20-dione><Dependence><Disease><Disorder><Drug Targeting><Early Diagnosis><Early treatment><Endocrine Gland Secretion><Environmental Health><Environmental Health Science><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epithelial Cells><Epithelium><Estrogens><Fallopian Tubes><Family><Female Reproductive Cancer><Follicular Fluid><Generalized Growth><Genotoxins><Goals><Gonadal Steroid Hormones><Growth><Gynecologic><Gynecologic Cancer><Gynecological Cancer><Homeostasis><Hormonal><Hormone Replacement Rx><Hormone replacement therapy><Hormones><Human><In Vitro><Induction of Apoptosis><Intracellular Communication and Signaling><Laboratories><Learning><Liquid substance><Liquor Folliculi><Malignant><Malignant - descriptor><Malignant Cell><Malignant Epithelial Cell><Malignant Female Reproductive System Neoplasm><Malignant Gynecologic Neoplasm><Malignant Gynecologic Tumor><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Female Reproductive System><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mammalian Oviducts><Manuscripts><Measures><Mediating><Mentors><Mentorship><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Micro-tubule><Microtubules><Mitochondria><Modeling><Modern Man><Mutagens><Neoplasm Metastasis><Neoplastic Cell Transformation><Neoplastic Processes><Oncogene Activation><Oncogenesis><Oncoprotein p53><Ovarian><Ovarian Follicle Antral Fluid><Ovarian Serous Adenocarcinoma><Ovarian Serous Carcinoma><Ovary Cancer><Ovulation><P53><PDX model><Paclitaxel><Paclitaxel (Taxol)><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Persons><Phosphoprotein P53><Phosphoprotein pp53><Physiologic><Physiological><Physiological Homeostasis><Platinum><Platinum Black><Position><Positioning Attribute><Post-Menopause><Post-menopausal Period><Postdoc><Postdoctoral Fellow><Postmenopausal Period><Postmenopause><Praxel><Precancerous Cells><Pregn-4-ene-3,20-dione><Pregnenedione><Premalignant Cell><Process><Progesterone><Programmed Cell Death><Protein Family><Protein TP53><Proteins><Pt element><Publishing><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Regulation><Research><Research Associate><Research Proposals><Risk Factors><Salpinx><Sampling><Science><Scientist><Secondary Neoplasm><Secondary Tumor><Secretory Cell><Serous Adenocarcinoma of the Ovary><Serous Carcinoma of the Ovary><Sex Hormones><Sex Steroid Hormones><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Stress><Survival Rate><TP53><TP53 gene><TRP53><Taxol><Taxol A><Taxol Konzentrat><Techniques><Testing><Therapeutic><Therapeutic Estrogen><Therapeutic Hormone><Therapeutic Progesterone><Therapeutically Targetable><Tissue Growth><Tissues><Training><Treatment Effectiveness><Tumor Burden><Tumor Cell><Tumor Load><Tumor Protein p53><Tumor Protein p53 Gene><Up-Regulation><Upregulation><Uterine Tubes><Woman><Writing><after menopause><anti-cancer research><bcl-x(L) protein><bcl-xlong protein><biological signal transduction><cancer cell><cancer metastasis><cancer research><cancer risk><cancer type><carcinogenesis><career><cell transformation><chemoresistant><chemotherapy resistance><chemotherapy resistant><conference><convention><crosslink><cultured cell line><design><designing><determine efficacy><diagnosis among females><diagnosis among women><diagnosis in females><diagnosis in women><diagnosis within females><diagnosis within women><early detection><early therapy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epidemiologic investigation><epidemiology study><evaluate efficacy><examine efficacy><experience><female diagnosis><fluid><following menopause><genotoxic agent><gonadal steroids><gynecologic malignancy><gynecological malignancy><homologous recombination><improved><in vivo><innovate><innovation><innovative><insight><liquid><malignancy><metaplastic cell transformation><mimetics><mitochondrial><mortality rate><mortality ratio><mouse model><murine model><mutant><necrocytosis><neoplasm recurrence><neoplasm/cancer><neoplastic cell><neoplastic transformation><novel><ontogeny><ovarian cancer><oviduct><p53 Antigen><p53 Genes><p53 Tumor Suppressor><past menopause><pathway><patient derived xenograft model><patient oriented outcomes><post-doc><post-doctoral><post-doctoral trainee><post-menopausal><postmenopausal><postmenopausal status><precancer><precancerous><premalignant><prevent><preventing><protein expression><protein p53><research associates><response to therapy><response to treatment><sex steroid><skills><standard of care><summit><symposia><symposium><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><taxane><therapeutic response><therapeutic target><therapy response><transformed cells><treatment response><treatment responsiveness><tumor><tumor cell metastasis><tumorigenesis><tumorigenic><verbal><women's diagnosis>