Program 1: Adaptive drug resistance

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Adaptive drug resistance precedes genetic drug resistance

With the surge of personalized medicine, a wave of molecularly targeted drugs enters the clinic. Although oncogene-targeting cancer drugs lead to rapid tumor shrinkage, durable clinical responses are rare. As therapy continues, tumor cells acquire numerous resistance-causing mutations which limit further therapeutic interventions.

Inspired and validated by real-world medicine, TOLREMO’s scientific founders discovered that modern cancer drugs targeting oncogenic signaling modules induce transcriptional adaptive resistance programs. This rewiring of transcriptional circuits is triggered long before drug resistance is manifested by irreversible genetic mutations.

Adaptive drug resistance represents a unique therapeutic window of opportunity: co-targeting transcriptional escape programs eliminates those cancer cells that would later on acquire irreversible, resistance-causing mutations. Preventing this early adaptation eradicates the seed of drug resistance already at the start of a cancer therapy. 

As part of the company’s unique drug resistance platform, TOLREMO has developed a proprietary high-throughput screening technology to identify small molecules that blunt the induction of cancer-drug triggered transcriptional reprogramming events. Tightly integrated biology/chemistry cycles have powered the rapid development of a proprietary, resistance-breaking compound series that is expected to enter preclinical testing as early as 2019.