At the vanguard of metabo-oncology

Drug candidate SDX-7320, which has already undergone Phase 1 study, offsets hyperglycemia caused by PI3K/Akt/mTOR cancer therapies and restores insulin sensitivity, according to recent preclinical research

October20th,2020
Jeffrey Bouley
CAMBRIDGE, Mass.—SynDevRx Inc., a clinical-stage oncology company, recently announced the completion of a series of preclinical studies that it says demonstrate its anticancer 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 drug candidate is already in the clinical stage, and it 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 cancer and melanoma), SDX-7320 displayed single-agent antitumor activity while improving metabolic dysfunction (in particular, hyperglycemia, insulin resistance and leptin resistance).1
 
Reportedly, SDX-7320 administration in normal mice2 prevented hyperglycemia and hyperinsulinemia—serious side effects of Piqray (Novartis’ PI3Kα inhibitor) and other drugs from these classes—that have been reported to lead to treatment resistance.3 In a xenograft model of ER+/Her2- breast cancer, SDX-7320 and Piqray administered together at low doses showed synergy at inhibiting tumor growth.
 
The company says that this 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.
 
“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,”4 said Jim Shanahan, co-founder and chief business officer of SynDevRx. “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 preclinical studies has been shown to cause resistance to these drug classes.5 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”2
 
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,” Shanahan added.
 
“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.5 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.

References
  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. 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)
  3. 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
  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
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