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Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL)

Award Number: R01CA257251
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL) - Abstract Philadelphia-positive acute lymhoblastic leukemia (Ph+ ALL) and Ph1-like B-ALL account for most cases of “high-risk” adult B-ALL. Current therapies with tyrosine kinase inhibitors (TKIs) have improved the outcome of Ph+ ALL, but resistance to TKIs develops rapidly in most patients. Ph1-like B-ALL is currently treated with intensive combination chemotherapy but disease relapse is common with a 5-year survival in only ~25% of patients. As a result, the prognosis of Ph+ ALL and Ph1-like B-ALL remains dismal. In previous studies, we showed that Ph+ and Ph1-like ALL cells exhibit a selective requirement for CDK6 expression while CDK4 expression is dispensable. CDK6 is the catalytic subunit of the cyclin D/CDK6 complex which is essential for the G1 to S-phase cell cycle transition and has kinase-independent growth-promoting effects in hematological malignancies. Our preliminary studies indicate that CDK6 silencing is more effective than CDK6 enzymatic inhibition in suppressing Ph+ ALL in mice. To block kinase-dependent and independent effects of CDK6, we have developed CDK4/6-targeted proteolysis-targeting chimera (PROTACs) that inhibit CDK4/6 enzymatic activity in vitro and promote the preferential degradation of CDK6 over CDK4 in Ph+ and Ph1-like ALL cells, providing durable suppression of CDK6 function. In this proposal, we will assess the requirement of CDK6 in Ph+ and Ph1-like ALL by comparing the effects of CDK6 degradation by PROTAC YX-2-107 and pharmacological inhibition using Palbociclib, an FDA-approved CDK4/6 inhibitor (Aim 1.1). We will also determine whether the more potent leukemia suppression induced by CDK6 down-regulation in comparison to CDK6 enzymatic inhibition can be explained by changes in gene expression induced selectively by CDK6 silencing. Such changes involve the histone deacetylase 1(HDAC1) gene and several others involved in mitochondrial metabolic pathways (Aims 1.2 and 1.3). Although we have been able to achieve high specificity of CDK6 versus CDK4 targeting and biological/therapeutic effects comparable/superior to Palbociclib ex vivo and in PDXs of Ph+ ALL, we will continue to improve our lead compound PROTAC YX-2-107 by medicinal chemistry approaches in order to develop derivatives with enhanced in vivo efficacy. In Aim 2, we will assess metabolic properties of select CDK6-degrading PROTACs and test their biological/therapeutic effects in Ph+ and Ph1-like ALL cells ex vivo and in mice injected with de novo or relapsed/TKI-resistant patient-derived Ph+/Ph1-like ALL cells. Collectively, our PROTAC-based approach which leverages the expertise in cancer biology and medicinal chemistry of the Calabretta and Salvino's laboratories holds promise to develop novel and more effective therapeutic agents for the treatment of CDK6-dependent high-risk B-ALL in pre-clinical PDX models and, potentially, in the clinic.


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 = $631,337 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	5	6/17/2025	NON-COMPETING CONTINUATION	$631,337
														Subtotal = $631,337

Issue Date FY: 2024 ( Subtotal = $599,770 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	4	6/25/2024	NON-COMPETING CONTINUATION	$599,770
														Subtotal = $599,770

Issue Date FY: 2023 ( Subtotal = $618,711 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	3	6/14/2023	NON-COMPETING CONTINUATION	$618,711
														Subtotal = $618,711

Issue Date FY: 2022 ( Subtotal = $618,711 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	2	6/23/2022	NON-COMPETING CONTINUATION	$618,711
														Subtotal = $618,711

Issue Date FY: 2021 ( Subtotal = $645,339 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	1	6/23/2021	NEW	$645,339
														Subtotal = $645,339

Grand Total All Awards = $3,113,868

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Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL)

Award Number: R01CA257251

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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