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Leveraging Protein Evolution to Eluc...

Marquez, Cesar P.

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Leveraging Protein Evolution to Elucidate Oncogenic Cytokine Signaling Axes and Develop Novel Therapeutics for Highly Lethal Cancers.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Leveraging Protein Evolution to Elucidate Oncogenic Cytokine Signaling Axes and Develop Novel Therapeutics for Highly Lethal Cancers./
作者:	Marquez, Cesar P.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	388 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-02, Section: B.
Contained By:	Dissertations Abstracts International82-02B.
標題:	Oncology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28121531
ISBN:	9798662513648

Leveraging Protein Evolution to Elucidate Oncogenic Cytokine Signaling Axes and Develop Novel Therapeutics for Highly Lethal Cancers.
Marquez, Cesar P.

Leveraging Protein Evolution to Elucidate Oncogenic Cytokine Signaling Axes and Develop Novel Therapeutics for Highly Lethal Cancers. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 388 p.

Source: Dissertations Abstracts International, Volume: 82-02, Section: B.

Thesis (Ph.D.)--Stanford University, 2020.

This item must not be sold to any third party vendors.

Pro-inflammatory cytokines in the tumor microenvironment (TME) can promote tumor growth, yet their value as therapeutic targets remains underexploited. Monoclonal antibodies have been the most widely used strategy to block ligand-receptor interactions and neutralize biological activity. An alternative approach involves engineering an extracellular fragment of a soluble receptor as a 'decoy' that binds to and sequesters the cognate ligand from activating cell surface receptors. Lung cancer is the leading cause of cancer-related death worldwide, and lung adenocarcinoma (LUAD) is the most common subtype. While approximately 30% of patients with LUAD harbor a mutation in KRAS, there are currently few targeted therapeutic options. Our group previously described a cytokine, cardiotrophin-like cytokine factor 1 (CLCF1), in a LUAD genetically-engineered mouse model (GEMM). CLCF1 is secreted by cancer-associated fibroblasts, binds to a receptor, ciliary neurotrophic factor receptor (CNTFR), on neoplastic cells, and promotes tumor growth. We first validated the functional significance of the CLCF1-CNTFR signaling axis in human LUAD. In collaboration with Dr. Jennifer Cochran, using directed evolution via yeast surface display technology, we generated a high affinity soluble receptor, eCNTFR-Fc, that neutralizes the ligand, CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple cell line and patient-derived tumor xenograft (PDTX) models and an autochthonous, highly aggressive GEMM of LUAD driven by activation of oncogenic Kras and loss of the tumor suppressor, Trp53. We also engineered an antagonistic ligand, ss6AA, which functions as a competitive antagonist of wild-type CLCF1 in tumor cell signaling and murine xenograft models. Mechanistic studies revealed that CLCF1 modulates ERK and STAT3 activity through SHP2, which in turn functions as an upstream regulator of both oncogenic and wild-type KRAS. As expected, abrogation of CLCF1 through eCNTFR-Fc is particularly effective in tumors driven by specific genotypes of mutant KRAS. This finding is significant given the recent observations highlighting the importance of upstream signaling molecules for both wild-type and oncogenic KRAS when the capacity to cycle between a GTP- and GDP-bound state is maintained. Indeed, we found that KRAS mutants most amenable to treatment also cycled more frequently between the two states. Our work, therefore, links novel cytokine signaling pathways with pro-tumorigenic downstream effectors. It also identifies a potential biomarker for further clinical development and provides an innovative therapeutic approach for a subset of tumors with limited available therapies. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially other tumor types, such as pancreatic ductal adenocarcinoma, in which CLCF1 is present in the TME. We decipher the mechanistic underpinnings of this pro-tumorigenic cytokine signaling axis and establish a link to oncogenic KRAS. We describe the development and preclinical testing of two first-in-class therapeutic candidates, an inhibitor (ss6AA) and a receptor decoy (eCNTFR-Fc), in multiple PDTXs and GEMMs. We demonstrate significant antitumor activity across a wide range of genetic subtypes, including KRAS-driven LUAD subsets, previously termed undruggable. Furthermore, we identified specific biomarkers that may portend increased sensitivity. These biomarkers could be used to stratify patients with tumors most likely to be inhibited by these agents in clinical trials.

ISBN: 9798662513648Subjects--Topical Terms:

751006
Oncology.
Subjects--Index Terms:

Pro-inflammatory cytokines

Leveraging Protein Evolution to Elucidate Oncogenic Cytokine Signaling Axes and Develop Novel Therapeutics for Highly Lethal Cancers.
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