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Anti-nucleolin aptamer AS1411: Applications in Kaposi's Sarcoma Associated Herpes Virus (KSHV) biology

Award Number: R21CA278641
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Anti-nucleolin aptamer AS1411: Applications in Kaposi's Sarcoma Associated Herpes Virus (KSHV) biology - Kaposi’s sarcoma-associated herpesvirus (KSHV), a member of the human γ-herpesvirus family is also termed as human herpesvirus type 8 (HHV-8). KSHV is an etiological agent of an endothelial tumor called Kaposi’s sarcoma (KS) and a highly aggressive lymphoproliferative B cell lymphoma called primary effusion lymphoma (PEL). KS is the most common vascular malignancy causing high morbidity and mortality in HIV-infected patients. PEL is a rare tumor of hematopoietic and lymphoid tissues and is associated with a poor prognosis. PEL cases have been dramatically reduced in the US since the widespread use of combined antiretroviral therapy (cART) but KSHV still causes significant mortality in the developing world. There is a critical need in KSHV targeting specific antiviral drugs, which are very well tolerated with no severe adverse events for immunocompromised patients with KSHV associated malignancies. KSHV exhibits two distinct phases in its life cycle. During latency, a minimal number of latency genes such as vFLIP (ORF71), vCyclin (ORF72), latency-associated nuclear antigen-1 (LANA-1; ORF73), and Kaposin are expressed. By contrast, during the lytic phase, KSHV expresses a wide array of immediate-early (IE), delayed-early (DE), and late genes; undergo active replication and produce virion progeny. KSHV has been shown to utilize multiple host growth factors, cytokines, angiogenic factors, and cell signaling and metabolism-related proteins for creating a beneficial environment for its replication, survival, and latency. Our exciting studies discovered that: 1) KS skin lesions express remarkably robust expression of nucleolin compared to healthy skin tissue; 2) KSHV de novo infection in primary endothelial cells induced a high level of nucleolin and phospho-nucleolin, and more importantly, 3) Incubation of KSHV infected cells with G- quadruplex forming anti-nucleolin aptamer AS1411 reduced KSHV latent (ORF73) and increased lytic (ORF50) gene expression and we obtained similar results in nucleolin silenced KSHV infected PEL cells. 4) AS1411 treatment was efficacious in inducing cell death in KSHV infected PEL cell lines. Based on our preliminary results, we hypothesize that KSHV induces host factor nucleolin to support its latency and life cycle and targeting nucleolin with AS1411 would have therapeutic potential in KSHV associated malignancies. To test this hypothesis, we have formulated two specific aims in which we will 1) To determine the regulatory mechanisms of nucleolin expression upon KSHV infection and its role in KSHV latency, and 2) To evaluate the chemotherapeutic potential of using AS1411 to treat KS and PEL. Our studies are significant and will have a positive impact by advancing the unexplored and novel targeted theranostic field of aptamers in KSHV biology and understanding their antiviral and anticancer potential can also be applied to other viral malignancies.


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 = $0 )
2026	2024	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Cancer Biology Research	000	2	12/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $182,325 )
2024	2024	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Cancer Biology Research	000	2	12/21/2023	NON-COMPETING CONTINUATION	$182,325
														Subtotal = $182,325

Issue Date FY: 2023 ( Subtotal = $218,790 )
2023	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Cancer Biology Research	000	1	12/21/2022	NEW	$218,790
														Subtotal = $218,790

Grand Total All Awards = $401,115

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Anti-nucleolin aptamer AS1411: Applications in Kaposi's Sarcoma Associated Herpes Virus (KSHV) biology

Award Number: R21CA278641

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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