Oxaliplatin, a frontline agent for colorectal cancer (CRC) treatment, has a mechanism of action that differs from other platinum drugs by blocking ribosome biogenesis rather than DNA damage. The target of oxaliplatin that induces ribosome biogenesis is not known. In spite of its clinical benefit, oxaliplatin has numerous adverse events and is often dose limited. Nonetheless, the preferential use of oxaliplatin in CRC raises the hypothesis that more specific and targeted inhibitors of ribosome biogenesis may be better tolerated and benefit patients with CRC. We discovered a novel molecule (MM017) with potent activity against CRC that specifically targets a factor required for ribosome biogene...

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Oxaliplatin, a frontline agent for colorectal cancer (CRC) treatment, has a mechanism of action that differs from other platinum drugs by blocking ribosome biogenesis rather than DNA damage. The target of oxaliplatin that induces ribosome biogenesis is not known. In spite of its clinical benefit, oxaliplatin has numerous adverse events and is often dose limited. Nonetheless, the preferential use of oxaliplatin in CRC raises the hypothesis that more specific and targeted inhibitors of ribosome biogenesis may be better tolerated and benefit patients with CRC. We discovered a novel molecule (MM017) with potent activity against CRC that specifically targets a factor required for ribosome biogenesis (Nuclear Valosin Like, NVL). Evaluation of MM017 in 902 unique cancer cell lines showed that its profile was highly correlated with oxaliplatin. We showed that NVL inhibition prevents ribosome biogenesis and upregulates the tumor suppressor p53, effects also observed with oxaliplatin. Critically, cells harboring MM017 resistant NVL2 mutations showed none of these effects confirming that they were on-target. The utility of oxaliplatin as frontline agent in CRC supports the rationale for testing NVL inhibitors for proof-of-concept studies in CRC. We hypothesize that NVL inhibition will provide a translatable strategy for CRC via a first-in-class mechanism of ribosome biogenesis inhibition compared to oxaliplatin with undefined molecular target. We assembled a multidisciplinary team and specified two aims: 1) medicinal chemistry and evaluation of NVL inhibitors, and 2) evaluation of in vivo drug tolerability and efficacy of optimized NVL inhibitors in CRC models. Our program has the potential to impact CRC treatment. Innovative aspects include: (1) the only known NVL inhibitors; (2) compound resistant NVL mutant tumors to help delineate on and off-target effects; and (3) germline compound resistant NVL mutant knock-in mice to help delineate on and off target toxicity in mice.

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