Drug resistance, metastasis, and tumor relapse continue to be leading causes of colorectal cancer (CRC)-related deaths. Current therapies only provide a limited increase in survival to the subset of advanced CRC patients that respond, demonstrating the need for innovative therapeutic strategies to improve outcome. Cancer stem cells (CSCs) are a subpopulation of tumor cells shown to be major drivers of tumor growth, metastasis, and relapse. Therefore, an effective cancer treatment could be one that destroys CSCs. LGR5 is a protein highly upregulated in CRC with low expression in normal healthy tissues and is found on the surface of CSCs. We generated anti-LGR5 antibody-drug conjugates (ADCs) ...

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Drug resistance, metastasis, and tumor relapse continue to be leading causes of colorectal cancer (CRC)-related deaths. Current therapies only provide a limited increase in survival to the subset of advanced CRC patients that respond, demonstrating the need for innovative therapeutic strategies to improve outcome. Cancer stem cells (CSCs) are a subpopulation of tumor cells shown to be major drivers of tumor growth, metastasis, and relapse. Therefore, an effective cancer treatment could be one that destroys CSCs. LGR5 is a protein highly upregulated in CRC with low expression in normal healthy tissues and is found on the surface of CSCs. We generated anti-LGR5 antibody-drug conjugates (ADCs) or “guided missiles” to seek and destroy LGR5+CSCs. ADCs are targeted antibodies linked to highly potent drugs that are only released inside cancer cells. We showed anti-LGR5 ADCs eliminated CRC tumors in mice without adverse effects, yet a fraction of the tumors eventually reappeared. Unfortunately, LGR5+ CSCs exhibit plasticity, or the ability to camouflage their appearance by continuously shifting between LGR5+ and LGR5- states to evade treatment. This plasticity presents a significant challenge to the development of an effective CSC-targeted therapy. Therefore, we propose to develop and evaluate an ADC combination treatment that destroys both LGR5+ CSCs and the LGR5- cancer cell that regenerate them. We will produce unique ADCs targeting a protein highly upregulated in CRC and found on the surface of the LGR5- cancer cells. We will evaluate safety and anti-tumor efficacy against a panel of CRC cell line and patient-derived tumor models. These ADCs will then be tested in combination with our anti-LGR5 ADCs to determine if destroying both LGR5+ CSCs and LGR5- cancer cells can improve treatment and prevent relapse by targeting plasticity. Results from this study may lead to the development of novel a targeted therapy and combination treatment strategy to eliminate CRC.

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