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HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL

Award Number: R01CA276167
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/22/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL - Project Summary The past two decades of cancer research have identified one or more drivers for most human malignancies. In addition, multiple cell death genes and pathways have been identified that normally protect the organism against developmental mutations or defects in genomic maintenance. These observations suggest that one might be able to rewire the transcriptional circuitry to cause the cancer cell to kill itself with its own driver. We have invented a new class of molecules that use Chemically Induced Proximity (CIP) to rewire the cancer cell such that the cancer driver activates proapoptotic pathways. We call these molecules Transcriptional Chemical Inducers of Proximity or TCIPs because they induce proximity or recruit a cancer driver to the promoters of proapopotic genes. For development of these two-sided, “bifunctional” molecules, we will focus on Diffuse Large Cell B Cell Lymphoma (DLBCL), using the master inhibitor of cell death, BCL6, as an anchoring transcription factor on the promoters of proapoptotic genes. For an activator we use any of several aberrantly-expressed transcription or epigenetic activators, to simultaneously derepress and activate proapoptotic genes. We have synthesized bifunctional small molecules that recruit transcriptional activators over-expressed in DLBCL to the promoters of proapoptotic genes normally bound and repressed by BCL6. In our preliminary studies, these molecules lead to rapid and robust killing of DLBCL that is superior to the best-in-class inhibitors and also specific for cells that over-express the targets of the bifunctional molecule. Using a strategy similar to genetic dominant gain-of-function mutations, TCIP can engage cancers with multiple drivers, thereby going beyond conventional inhibitors and degraders. Because bifunctional molecules rely on two separately overexpressed proteins, TCIP takes advantage of the natural, fundamental basis of transcriptional specificity to provide precise, predictable and selective killing of cancer cells. To further develop this approach, we will first optimize these molecules for stability, solubility and specificity of killing of DLBCL. Secondly, we will define the mechanism by which they produce robust and rapid killing. Finally, we will test them in established PDX models. Our studies will involve a multidisciplinary approach drawing on expertise in chemistry, clinical lymphoma treatment, cancer biology and genomic biology. If successful, we will lay the foundation for a new concept in the treatment of lymphoma, and more broadly, cancer chemotherapy, that is more specific than many existing approaches. The use of a novel dominant gain-of-function strategy by TCIPs addresses the issue of treatment of cancers, such as DLBCL, that have multiple, concurrent drivers.


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: 2026 ( Subtotal = $594,658 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	001	4	4/27/2026	NON-COMPETING CONTINUATION	$59,466
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	4	12/3/2025	NON-COMPETING CONTINUATION	$535,192
														Subtotal = $594,658

Issue Date FY: 2025 ( Subtotal = $614,155 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	001	3	6/3/2025	NON-COMPETING CONTINUATION	$61,415
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	3	11/22/2024	NON-COMPETING CONTINUATION	$552,740
														Subtotal = $614,155

Issue Date FY: 2024 ( Subtotal = $510,464 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$26,867
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	2	11/7/2023	NON-COMPETING CONTINUATION	$483,597
														Subtotal = $510,464

Issue Date FY: 2023 ( Subtotal = $439,147 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	1	12/22/2022	NEW	$439,147
														Subtotal = $439,147

Grand Total All Awards = $2,158,424

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HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL

Award Number: R01CA276167

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/22/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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