Saturday, November 23, 2024 11/23/2024

Evaluation of Novel Dually Targeted Kinase Inhibitors for Therapy of Adult and Pediatric High-Grade Glioma

Award Number: R33NS111058
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY High grade gliomas in both adults and children confer very poor prognosis, with median survival rates under two years post diagnosis. Amplification of epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), as well as mutations in the PI3K/AKT/mTOR pathway are frequent and can be targeted by kinase inhibitor based strategies. EGFR inhibition has been tested clinically, but responses have been limited. Inadequate target engagement, perhaps due to poor blood brain barrier penetrance, as well as downregulation or circumvention of the target in recurrent tumors, are amongst mechanisms cited for lack of efficacy of EGFR-targeted agents. Combination strategies using PI3K and MAPK inhibitors are promising, and can overcome acquired resistance to single agents in GBM. Advantages of using a single molecule to target multiple kinases include reduced risks of drug interactions, a single pharmacokinetic profile for optimization of dosing, and increased potential for overcoming drug resistance. Therefore, the development of therapeutics that target more than one kinase, identification of biomarkers of response and careful evaluation of BBB permeance are imperative to improving patient outcomes. Employing a computational modeling approach, we exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to design small molecules that simultaneously inhibit both kinases in a selective manner. We hypothesize that this polypharmacology approach will provide better efficacy in vitro and in vivo compared to multi-drug combination strategies. Preliminary data generated in human glioblastoma and patient derived pediatric diffuse intrinsic pontine glioma (DIPG) lines shows potent cytotoxic effects of these dually targeted agents relative to targeting of EGFR alone or PI3K alone. Furthermore, we have identified unique metabolic features of the inhibitors, indicating suppression of both glycolytic pathways and oxidative phosphorylation, which is not seen with clinically relevant EGFR or PI3K inhibitors. We posit that this will lead to the development of metabolomics based biomarkers. In Year 1, in the R61 phase of this application, we will further optimize the pharmaceutical features of this chemical series of compounds to increase the likelihood of blood-brain barrier (BBB) penetrance. We have generated key preliminary data showing that MTX-241 possess critical attributes for BBB permeability. Therefore we will use in vivo models to test MTX-241, while simultaneously synthesizing and evaluating 15-20 structural analogs of MTX-241. The R33 phase of the proposal will be carried out in Years 2 and 3, whereupon we will focus on in vivo evaluation of the two most promising candidates identified using orthotopic models to address anti-tumor efficacy, blood brain barrier permeance, and biomarkers of drug action. These studies have been designed to support our hypothesis that a single inhibitor with dual specificity for EGFR and PI3K represents a rationale and promising treatment strategy for recurrent adult and pediatric HGG with high translational potential.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = -$5,845 )
2024	2021	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/5/2024	NON-COMPETING CONTINUATION	-$5,845
														Subtotal = -$5,845

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $368,074 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/2/2021	NON-COMPETING CONTINUATION	$365,801
2021	2020	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/8/2021	EXTENSION WITH OR WITHOUT FUNDS	$2,273
														Subtotal = $368,074

Issue Date FY: 2020 ( Subtotal = $335,679 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/28/2020	EXTENSION WITH OR WITHOUT FUNDS	$335,679
														Subtotal = $335,679

Grand Total All Awards = $697,908

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Evaluation of Novel Dually Targeted Kinase Inhibitors for Therapy of Adult and Pediatric High-Grade Glioma

Award Number: R33NS111058

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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