Clinical Drug Candidate SDX-7320 Offsets Hyperglycemia Caused by PI3K/Akt/mTOR Cancer Therapies and Restores Insulin Sensitivity, SynDevRx's Preclinical Studies Show
Preclinical data indicate that SDX-7320 inhibits tumor growth and counteracts treatment-induced metabolic dysfunction, a safety concern that can interrupt PI3K/Akt/mTOR cancer therapy and lead to treatment resistance in tumors.
CAMBRIDGE, MASS. (PRWEB) OCTOBER 21, 2020
SynDevRx, Inc., a clinical-stage oncology company, announces the completion of a series of preclinical studies demonstrating that its anti-cancer drug candidate, SDX-7320, inhibits PI3K/Akt inhibitor-induced hyperglycemia and subsequent hyperinsulinemia in normal mice and inhibits tumor growth in multiple models of HR+ breast cancer. The company’s ongoing research places them at the vanguard of metabo-oncology, an emerging field of cancer research that focuses on the role metabolic hormones play in the development and progression of many common cancers, as well as tumor resistance developed in response to certain treatments.
SDX-7320 inhibits MetAP2, a clinically validated target that plays a key role in tumor growth, metastasis, angiogenesis, and metabolic dysfunction. In a series of efficacy and safety studies in a variety of syngeneic cancer models (breast, melanoma), SDX-7320 displayed single agent anti-tumor activity while improving metabolic dysfunction (in particular, hyperglycemia, insulin resistance and leptin resistance).  SDX-7320 prevented the hyperglycemia and hyperinsulinemia associated with Piqray® (Novartis’ 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 tumor growth.
“Piqray is an important new therapy for patients with HR+/Her2-, metastatic breast cancer whose tumors have a mutation in the PIK3CA gene. However, drugs that target the PI3K/Akt pathway frequently cause hyperglycemia in patients, especially those with high baseline fasting glucose, HbA1c, insulin resistance, pre-diabetes, type 2 diabetes or obesity.  Treatment-induced hyperglycemia has been reported as a safety concern that can lead to dose interruptions and/or drug holidays. In addition, the treatment-induced hyperglycemia leads to hyperinsulinemia which in pre-clinical studies has been shown to cause resistance to these drug classes.”  said Jim Shanahan, Co-Founder and Chief Business Officer of SynDevRx. “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, capivasertib (AstraZeneca) showed that SDX-7320 also attenuated treatment-induced hyperglycemia (in normal mice), and inhibited tumor growth in a xenograft model of HR+/Her2+ breast cancer. “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 tumor growth inhibition,” he continued.
“Companies developing drugs targeting the PI3K/Akt/mTOR pathway may experience toxicity issues related to drug-induced hyperglycemia followed by hyperinsulinemia, eventually resulting in resistance to therapy.  SDX-7320 has demonstrated that it can help to address this problem in vivo,” said Brad Carver, Co-Founder, President and CEO of SynDevRx. “Our data suggests that drugs targeting the PI3K/Akt/mTOR pathway should see better safety and better anti-tumor activity by administering SDX-7320 in combination with those agents.”
To test this hypothesis, SynDevRx intends to commence Phase 2 studies in late-stage ER+, Her2- breast cancer patients. To learn more about SynDevRx clinical trials, visit: http://www.syndevrx.com/.
1. Abstract 4919: Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer. Cornelius P, Petersen JS, Mayes B, Turnquist D, Sullivan K, Anderson-Villaluz A, Lutz R, Little S, Slee A, Carver BJ, Shanahan J. Cancer Res July 1 2018 (78) (13 Supplement) 4919; DOI: 10.1158/1538-7445.AM2018-4919
2. Abstract 2147: Synergistic inhibition of MCF-7 mammary gland tumor growth with Piqray®(alpelisib) plus SDX-7320, a novel polymer-conjugated methionine aminopeptidase 2 (MetAP2) inhibitor. Cornelius P, Mayes B, Little S, Slee A, Nir R, Nir A, Carver B, Shanahan J. Cancer Res February 14 2020 80 (4 Supplement) P3-11-13-P3-11-13; DOI:10.1158/1538-7445.SABCS19-P3-11-13
3. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904: Fox et al., Breast Cancer Research volume 15, Article number: R55 (2013)
4. Rugo et al, 2020, Annals of Oncology: https://doi.org/10.1016/j.annonc.2020.05.001
5. Hopkins, B.D., Pauli, C., Du, X. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018). https://doi.org/10.1038/s41586-018-0343-4
SynDevRx is a privately held clinical stage biopharmaceutical company based in Cambridge, Massachusetts focused on the research and development of treatments that address the unique and underserved needs of cancer patients with systemic metabolic dysfunction – i.e., metabo-oncology. Obesity, pre-diabetes and type 2 diabetes are known to worsen cancer patients’ prognosis, but oncologists have no specific tools to deal with systemic metabolic complications except for changes in diet and exercise. SynDevRx intends to initiate a series of Phase 2 clinical studies of its drug candidate SDX-7320 to address this major, unmet medical need. Preclinical studies have shown that SDX-7320 reduces tumor growth and angiogenesis, helps to control aberrant metabolic hormone signaling, and reduces treatment resistance to certain standard cancer therapies in metabolically sensitive cancers. SDX-7320 is being developed for use in combination with standard of care therapies for a variety of solid tumors.