Colorectal cancer is still a major cause of cancer-related death in the world and only a small subset ofpatients benefits from therapy by immune checkpoint inhibitors. Antibody-drug conjugates (ADCs) aremonoclonal antibodies (mAbs) that are covalently linked to cell-killing drugs and have emerged as amajor modality in anti-cancer treatment. This approach combines high specificity of mAbs against theirantigen 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 majormodality of cancer therapeutics with several ADCs approved in the last few years. Leucine-rich repeatcontaining, G protein-coupled receptor 4, 5 and 6 (LGR4-6) are three related receptors that are highlyupregulated in colorectal cancers. They bind R-spondins (RSPOs), a group of secreted proteins withhigh affinity and potentiate Wnt signaling. Aberrant RSPO-LGR signaling plays critical roles in tumorformation, progression, and drug resistance. In particular, LGR5 is enriched in cancer stem cells ofcolon 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 tocompletely eradicate tumors due to cancer cell plasticity. Remarkably, LGR5-negative cells stillexpress LGR4 or LGR6 or both. We reasoned that simultaneous targeting LGR4-6 may overcomecancer cell plasticity and drug resistance. Recently, we demonstrated that a mutated form of RSPOcan bind to LGR4-6 with high affinity without potentiating Wnt signaling. Drug conjugates of RSPOmutant fused to IgG1-Fc domain was able to inhibit tumor cell growth in vitro and in vivo. We havenow generated a pyrrolobenzodiazepine dimer (PBD)-based drug conjugate of an RSPO2 mutant thatshowed potent anti-tumor effect in colon cancer models in vitro and in vivo. In this proposal we willevaluate the drug conjugate in a series of colon cancer models in vitro and in vivo and determine itstolerability in mice. These results and conclusions may, for the first time, validate PBD-conjugatedRSPO-Fc protein as a novel approach for simultaneous targeting of LGR4-6 for colorectal cancertreatment and identify drug candidates for further development.
Public Health Relevance Statement: Public Health Relevance Statement:
Project title: Development of drug conjugates of R-spondin peptibodies for the treatment of
colorectal cancer.
Contact P.I. Jie Cui
Statement: Colorectal cancer remains a major cause of cancer-related death in the world. The
proposed study aims to establish proof-of-principle in preclinical models for the use of drug conjugates
of R-spondin peptibodies against a group of related receptors that are highly upregulated in colorectal
cancer. The work may lead to the discovery and development of a novel class of therapeutics for the
treatment of colorectal cancer patients.
Project Terms: <7S Gamma Globulin> | | | | | 