Anticancer candidate inhibits drug-induced hyperglycaemia

Monday, 26 October, 2020

Anticancer candidate inhibits drug-induced hyperglycaemia

A new anticancer drug candidate, developed by clinical-stage oncology company SynDevRx, offers a way to inhibit both tumour growth and drug-induced hyperglycaemia in multiple models of HR+ breast cancer, as demonstrated in a recent series of preclinical studies.

Many types of cancer are commonly treated with PI3K/Akt therapies, but these drugs often induce hyperglycaemia (high blood glucose) — especially in patients who already have metabolic complications such as obesity, pre-diabetes or type 2 diabetes. Hyperglycaemia can lead to drug holidays and, in serious cases, can cause treatment-induced resistance in tumours.

Aiming to address the interplay between metabolic dysfunction and cancer, SynDevRx developed SDX-7320, which works by inhibiting MetAP2 — a clinically validated target that plays a key role in tumour growth, metastasis, angiogenesis and metabolic hormone dysfunction.

In a series of efficacy and safety studies in a variety of syngeneic cancer models (breast, melanoma), SDX-7320 displayed single agent anti-tumour activity while improving metabolic dysfunction (in particular, hyperglycaemia, insulin resistance and leptin resistance). SDX-7320 prevented the hyperglycaemia and hyperinsulinemia associated with Piqray (Novartis’s PI3Kα inhibitor) administration in normal mice — serious side effects of drugs from these classes that have been reported to lead to treatment resistance. Furthermore, in a xenograft model of ER+/Her2- breast cancer, SDX-7320 and Piqray (alpelisib), administered together at low doses, showed synergy at inhibiting tumour growth.

“Piqray is an important new therapy for patients with HR+/Her2-, metastatic breast cancer whose tumours have a mutation in the PIK3CA gene,” said Jim Shanahan, co-founder and Chief Business Officer of SynDevRx. “However, drugs that target the PI3K/Akt pathway frequently cause hyperglycaemia in patients, especially those with high baseline fasting glucose, HbA1c, insulin resistance, pre-diabetes, type 2 diabetes or obesity.

“Treatment-induced hyperglycaemia has been reported as a safety concern that can lead to dose interruptions and/or drug holidays. In addition, the treatment-induced hyperglycaemia leads to hyperinsulinemia, which in preclinical studies has been shown to cause resistance to these drug classes. Baseline systemic metabolic complications, such as obesity, pre-diabetes or type 2 diabetes, were reported to correlate with and predict worse outcomes for many breast cancer patients taking Piqray.”

Preclinical studies of SDX-7320 with another drug from the PI3k/Akt class, the Akt/mTOR inhibitor known as capivasertib (AstraZeneca), showed that SDX-7320 also attenuated treatment-induced hyperglycaemia (in normal mice) and inhibited tumour growth in a xenograft model of HR+/Her2+ breast cancer. According to Shanahan, “Our preclinical data with alpelisib (Piqray) and capivasertib suggests that SDX-7320 may make drugs targeting the PI3k/Akt/mTOR pathway safer and more effective by controlling blood glucose and insulin levels in combination with tumour growth inhibition.”

SynDevRx will soon commence Phase 2 studies in late-stage ER+/Her2- breast cancer patients.

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