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Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy

Award Number: R01CA259188
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy - PROJECT SUMMARY Anaplastic large cell lymphoma (ALCL) comprises a collection of mature T-cell neoplasms that share elevated expression of CD30 and anaplastic cytology. ALCL subtypes are divided into two classes based on the status of anaplastic lymphoma kinase (ALK), ALK+ and ALK-. While ALK+ ALCL is relatively homogeneous, ALK- ALCL represents a heterogeneous group comprising systemic ALK negative and primary cutaneous ALCL (pC-ALCL). The recently recognized breast implant-associated (BIA) ALCL, which arises in the seroma cavity surrounding breast implants, was acknowledged as a distinct clinical and pathological entity that shares morphologic features with ALK- ALCL. Current therapeutic strategies for ALCL are largely based on aggressive B-cell lymphoma regimens. However, the outcomes are generally much worse in patients with ALK- ALCL than in those with ALK+ ALCL. Thus, there is a need to develop novel, preferably small molecule-based targeted therapies for these lymphoid malignancies, especially in ALK- and BIA ALCL cases. A major barrier to this goal is the lack of a systematic and comprehensive understanding of the deep molecular characteristics of ALK- and BIA ALCL pathology, which is clearly needed in order to identify critical therapeutic vulnerabilities. To address the gaps in knowledge, we applied an unbiased high throughput CRISPR screening in ALCL, and identified an unexpected role of the IL-1R-MyD88 pathway in supporting ALK- and BIA ALCL. The IL-1R signaling pathway is a key mediator of immunity and inflammation and has been shown to play a critical role in many solid tumors; however, its role in lymphoid malignancies has not been established. Indeed, our preliminary studies provide the first unequivocal evidence that IL-1R1 pathway plays an essential role in supporting ALK- and BIA ALCL cell survival. Clinically, we found that IL-1 receptor and IL-1α expression are consistently elevated in primary ALK- cases, and this is correlated with IL-1R signaling activation (p-IRAK4 level) in primary samples. Moreover, using RNA-seq analysis, we identified a set of IL-1R pathway regulated genes in ALK- ALCL that overlapped significantly with signatures reflecting JAK-STAT3 activity and TH17/TH1 phenotyping. Finally, a highly specific IRAK4 inhibitor shows promising activity against ALK- and BIA ALCL in vitro and in a mouse xenograft model. Altogether, these findings provide strong support for our hypothesis that the IL-1R pathway promotes ALK- and BIA ALCL pathogenesis, and that targeting this pathway could be a novel therapeutic strategy in these diseases. In this study, we will test our hypothesis through the following aims: 1) Elucidation of the exact role of IL-1R pathway in ALK- and BIA ALCL, 2) Understanding of mechanisms regulating this pathway and its relationship to recurrent genetic lesions in ALCL, and 3) Validation of the IL-1R pathway as a novel therapeutic target in these malignancies. The proposed studies should provide critical insights into the molecular circuitry that drives these types of ALCL and, consequently, result in the development of novel targeted therapeutic strategies for these distinct lymphoproliferative disorders.


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 = $410,489 )
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	5	4/10/2025	NON-COMPETING CONTINUATION	$369,440
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	5	5/26/2025	NON-COMPETING CONTINUATION	$41,049
														Subtotal = $410,489

Issue Date FY: 2024 ( Subtotal = $383,481 )
2024	2024	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	4	4/5/2024	NON-COMPETING CONTINUATION	$383,481
														Subtotal = $383,481

Issue Date FY: 2023 ( Subtotal = $395,588 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	3	3/24/2023	NON-COMPETING CONTINUATION	$395,588
														Subtotal = $395,588

Issue Date FY: 2022 ( Subtotal = $415,375 )
2022	2022	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	2	3/30/2022	NON-COMPETING CONTINUATION	$407,062
2022	2022	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	2	9/1/2022	NON-COMPETING CONTINUATION	$8,313
														Subtotal = $415,375

Issue Date FY: 2021 ( Subtotal = $417,520 )
2021	2021	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	1	4/6/2021	NEW	$417,520
														Subtotal = $417,520

Grand Total All Awards = $2,022,453

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Investigating the IL-1R Pathway in Anaplastic Large Cell Lymphoma for Targeted Therapy

Award Number: R01CA259188

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/06/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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