CAMKK2 Promotes Prostate Cancer Progression through Independent Intrinsic and Extrinsic Roles

Simple item page
dc.contributor.advisorZhang, Xiaoliu Shaun
dc.contributor.committeeMemberFrigo, Daniel E.
dc.contributor.committeeMemberUmetani, Michihisa
dc.contributor.committeeMemberChung, Sang-Hyuk
dc.contributor.committeeMemberCoarfa, Cristian
dc.creatorPulliam, Thomas Loyd
dc.creator.orcid0000-0002-5440-1008
dc.date.accessioned2021-09-22T17:44:33Z
dc.date.createdMay 2021
dc.date.issued2021-05
dc.date.submittedMay 2021
dc.date.updated2021-09-22T17:44:35Z
dc.description.abstractCalcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is emerging as a promising therapeutic target due to its roles in driving several pathological conditions including metabolic disorders, osteoporosis, Alzheimer’s disease and multiple cancer types. Recently, it has been discovered that CAMKK2 also regulates the immune response to infection and promotes an immunosuppressive tumor microenvironment to extrinsically aide certain cancers. CAMKK2 is a calcium/calmodulin-activated master kinase with a restricted expression profile, but when expressed, it can potentially drive pathological conditions. This dissertation will cover CAMKK2’s intrinsic function in prostate cancer and an emerging mechanism of resistance that could guide the development of future rationale treatment combinations. Prostate cancers overcome CAMKK2 knockout (KO) or knockdown (KD) by increasing angiogenesis to sustain tumor growth in vivo. We discovered this was due to a change in expression of two angiogenesis regulatory genes, thrombospondin-1 and angiopoietin-2, both previously reported as mediators of a pro-angiogenic “switch” necessary to promote cancer progression. We leveraged a well-known clinical inhibitor of angiogenesis, bevacizumab, with CAMKK2 KO in preclinical animal models of castration-resistant prostate cancer (CRPC) to profoundly reduce tumor growth and increase overall survival. This dissertation will also cover CAMKK2’s extrinsic role in aiding prostate cancer progression via immune suppression and a possible new role via macrophage-mediated EMT. Systemic Camkk2 KO in host mice slowed tumor growth macrophage-mediated EMT. Systemic Camkk2 KO in host mice slowed tumor growth in two separate syngeneic prostate cancer models. Decreased activated T-cells and greater infiltration of tumor supporting M2 macrophages in Camkk2 wild-type (WT) mice suggests CAMKK2 plays a functional role in regulating the immune system to support prostate cancer. Finally, this dissertation will cover problems plaguing the currently accepted inhibitor of CAMKK2, STO-609, and efforts to design a novel selective and potent inhibitor of CAMKK2 to take its place. With our collaborators, we have used the approach of hinge-binder scaffold modification to discover a new CAMKK2 inhibitor, YL-36, with a 10 fold increase in potency over STO-609 as well as vastly improved selectivity. Together, we solidify CAMKK2’s role as an oncogenic driver of prostate cancer intrinsically, provide insights into CAMKK2’s emerging tumor extrinsic roles in driving cancer, and finally describe a combinatorial approach of treatment with angiogenesis and CAMKK2 inhibitors simultaneously to increase the efficacy of CAMKK2 inhibitors once they reach the clinic.
dc.description.departmentBiology and Biochemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/8271
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectCAMKK2
dc.subjectprostate
dc.subjectcancer
dc.subjectangiogenesis
dc.titleCAMKK2 Promotes Prostate Cancer Progression through Independent Intrinsic and Extrinsic Roles
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2023-05-01
local.embargo.terms2023-05-01
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentBiology and Biochemistry, Department of
thesis.degree.disciplineBiology
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
PULLIAM-DISSERTATION-2021.pdf
Size:
3.22 MB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 2 of 2
No Thumbnail Available
Name:
PROQUEST_LICENSE.txt
Size:
4.43 KB
Format:
Plain Text
Description:
Download
No Thumbnail Available
Name:
LICENSE.txt
Size:
1.81 KB
Format:
Plain Text
Description:
Download

Collections

Published ETD Collection