Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

Summary Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail—vorinostat, pindolol, tofacitinib—that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.

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Crystal harvesting remains the bottleneck in protein crystallography experiments and is the rate-limiting step for many structure determination, high-throughput screening and femtosecond crystallography studies. Huge progress has been made towards the automation of high-throughput crystallization, even for membrane proteins. Moreover, free electron lasers and fourth generation synchrotrons support extraordinarily rapid rates of data acquisitions and put further pressure on the crystal-harvesting step. Here [1], a simple solution is reported in which crystals can be acoustically harvested from slightly modified MiTeGen In Situ-1 crystallization plates. Acoustic harvesting uses the automated and keyboard driven acoustic droplet ejection (ADE) technology, in which an acoustic pulse ejects each crystal out of its crystallization well, through a short air column and directly onto a micro-mesh. Crystals can be individually harvested or can be serially combined with a chemical library such as a fragment library.