ARQ-621

Triple-negative breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-negative subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ∼400 anticancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anticancer compounds that significantly impaired cell survival across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic natural product licochalcone A was of interest, since TNBCs are unresponsive to estrogenic therapies, indicating that licochalcone A was likely acting through another target. Using chemoproteomic profiling approaches, we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation. We also more broadly performed metabolomic profiling to map additional metabolic mechanisms of compounds that impair TNBC pathogenicity. Overlaying lipidomic profiling with drug responses, we find that deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments. We thus put forth two unique metabolic nodes that are targeted by drugs or drug candidates that impair TNBC pathogenicity. Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers of TNBC pathogenicity.

Array is also looking at a potential biomarker, alpha-1 acidic glycoprotein (AAG), which is often elevated in people with multiple myeloma.AAG is a ′cleanup′ protein in the blood serum that can bind to ARRY-520, rendering it ineffective.In a 32-person trial in which patients with myeloma received ARRY-520 alone, 5 of the 21 participants with low AAG levels showed a reduction in M protein that lasted for more than 8 mo on average, whereas none of the 5 participants with high AAG levels experienced such a favorable response.According to Koch, the findings, which will also be presented at the Dec. ASH meeting, suggest that AAG levels could help indicate who might be a good candidate for the drug. "There are very few mechanisms that show such strong single-agent activity," he says.Array is not the only company that has faith in the KSP pathway.At least two other companies, ArQule and Alnylam Pharmaceuticals, both based in the Boston area, are developing compounds that target KSP.ArQule′s ARQ 621 is being tested in both hematol. and solid tumor cancers, while Alnylam′s ALN-VSP is focused on liver cancer.ALN-VSP is unique among these drugs, as it does not target the KSP protein directly, but uses RNA interference to prevent it from being expressed in the first place.(ARQ 621, like ARRY-520, is a typical small mol. that′s administered i.v.) So far, both have only been tested in phase 1 trials.At first, ARRY-500 will probably be used only in people with myeloma who have failed on other drugs.But Andy Robbins, Array′s senior vice-president of com. and strategy, hopes that KSP inhibitors like ARRY-520 will one day form a frontline therapy, alongside the two entrenched classes of therapies: immunomodulators such as Revlimid (lenalidomide) and proteosome inhibitors such as Kyprolis and Velcade. "We have the potential to be a third backbone treatment," he says.