Development of drug conjugates of r-spondin peptibodies for the treatment of colorectal cancer
Ended Project Grant Awarded Last action
- Award ID
- R41CA281553
- Recipient
-
Wntrix, Inc. UEI HE6LHLBVCLY5
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $400,000
Award facts
- Assistance listing
- 93.395 Cancer Treatment Research
- Completion date
- Originally
- Place of performance
- Texas, USA
Award details come from USAspending.gov.
Description
- Abstract
- Colorectal cancer is still a major cause of cancer-related death in the world and only a small subset of patients benefits from therapy by immune checkpoint inhibitors. Antibody-drug conjugates (adcs) are monoclonal antibodies (mabs) that are covalently linked to cell-killing drugs and have emerged as a major modality in anti-cancer treatment. This approach combines high specificity of mabs against their antigen targets with highly potent cytotoxic drugs, resulting in "armed" mabs that deliver the payload (drug) to tumor cells with enriched levels of the antibody target. The approach has become a major modality of cancer therapeutics with several adcs approved in the last few years. Leucine-rich repeat containing, g protein-coupled receptor 4, 5 and 6 (LGR4-6) are three related receptors that are highly upregulated in colorectal cancers. They bind r-spondins (rspos), a group of secreted proteins with high affinity and potentiate WNT signaling. Aberrant rspo-LGR signaling plays critical roles in tumor formation, progression, and drug resistance. In particular, LGR5 is enriched in cancer stem cells of colon cancer and LGR5-positive cells drive tumor growth and metastasis. However, LGR5-positive and -negative cells can interconvert and adcs targeting LGR5 inhibited tumor growth but failed to completely eradicate tumors due to cancer cell plasticity. Remarkably, LGR5-negative cells still express LGR4 or LGR6 or both. We reasoned that simultaneous targeting LGR4-6 may overcome cancer cell plasticity and drug resistance. Recently, we demonstrated that a mutated form of rspo can bind to LGR4-6 with high affinity without potentiating WNT signaling. Drug conjugates of rspo mutant fused to IGG1-FC domain was able to inhibit tumor cell growth in vitro and in vivo. We have now generated a pyrrolobenzodiazepine dimer (PBD)-based drug conjugate of an RSPO2 mutant that showed potent anti-tumor effect in colon cancer models in vitro and in vivo. In this proposal we will evaluate the drug conjugate in a series of colon cancer models in vitro and in vivo and determine its tolerability in mice. These results and conclusions may, for the first time, validate PBD-conjugated rspo-FC protein as a novel approach for simultaneous targeting of LGR4-6 for colorectal cancer treatment and identify drug candidates for further development.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Original award | $400,000 |
Quick answers
Who received award R41CA281553?
R41CA281553 was awarded to Wntrix, Inc. by National Cancer Institute (National Institutes of Health) on May 1, 2023.
How much is award R41CA281553 worth?
$400,000 has been obligated on R41CA281553.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award