The Link Between Cancer and Metabolic Dysfunction
SynDevRx is working to address the unmet medical need in the field of metabo-oncology by developing treatments for cancer patients who are overweight or have systemic metabolic dysfunction.188金宝搏备用recently spoke with Jim Shanahan, co-founder, vice president of business development and director ofSynDevRx, to explore the impact of metabolic dysfunction on treatment outcomes and learn more about the company’s lead compound SDX-7320.
Laura Lansdowne (LL): Could you tell us about the link between cancer and metabolic hormone dysfunction?
Jim Shanahan (JS):It is commonly understoodthat obesity increases the risk for certain cancers. What drives this effect has to do with adipose (fat) tissue, which produces a variety of hormones and cytokines that, when dysregulated (as in obesity),stimulate tumor growthand metastasis. Two of the most common and potent metabolic drivers of cancer are insulin and leptin.
Insulin, produced by the pancreas in response to elevated blood glucose, stimulates tumor growthvia the PI3K/Akt/mTOR pathway.Insulin resistance, often seen in people who are obese or even simply those who have excess visceral adipose tissue (i.e., belly fat) is a pathological state where peripheral tissues (i.e., liver, adipose tissue, skeletal muscle) are less responsive or unresponsive to insulin, leading to chronically high levels of fasting insulin.In the US, an estimated88 millionpeople have insulin resistance and in the UK, an estimated12 million2型糖尿病的风险吗.This is not a new problem; almost 20 years ago, Dr Pamela Goodwin, a leader in the field,reported that“High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored.” A largerecent studyof > 20,000 post-menopausal women showed a significantly increased risk of cancer-specific mortality with elevated insulin resistance. Despite the abundance of research showing insulin is a bad actor in cancer, insulin levels are rarely ever measured in cancer patients.
Leptin is an adipocyte-derived hormone whose levels are in directproportion to fat mass. Leptin acts as a primary regulator of normal metabolic physiology and energy metabolism. The binding of leptin to its specific receptoractivates multiple signaling pathways,includingJanus激酶2 (JAK2) /信号传感器和一个ctivator of transcription 3 (STAT3), insulin receptor substrate (IRS)/phosphatidylinositol 3 kinase (PI3K), SH2-containing protein tyrosine phosphatase 2 (SHP2)/mitogen-activated protein kinase (MAPK) and 5' adenosine monophosphate-activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC), in the central nervous system and peripheral tissues. Importantly many of these pathways are validated oncogenic pathways commonly targeted by cancer drugs since theyoverlap with growth factor signaling(e.g.,VEGF and bFGF,Her2). More recently itwas found thatleptin receptors are highly expressed on cancer cells and leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis and induce anti-cancer drug resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), ortumor-initiating cells,leading to the formation of metastatic lesions.
Conversely, in patients with metabolic dysfunction, the secretion of a key protective adipokine calledadiponectin, is reduced. Adiponectinincreases insulin sensitivity, thereby reducing levels of fasting insulin. Through its receptor interactions, adiponectin may exert its anti-carcinogenic effects including regulating cell survival, apoptosis and metastasis via aplethora of signaling pathways. Adiponectin has also been shown todirectly inhibit tumor growthand counter-act the tumor-promoting effects of leptin. Furthermore, levels of circulating adiponectin areinversely associated with survival outcomesin breast cancer.
The role that metabolic syndrome and metabolic hormones play in cancer issignificant yet frequently ignoredand entirely underappreciated.
LL: Some anti-cancer drugs can cause metabolic dysfunction – what impact does this have on efficacy and overall treatment success?
JS:The short answer is that metabolic dysfunction (independent of origin) has a decidedly negative impact on treatment outcomes and patient quality of life. Manycommon anti-cancer treatments induce insulin resistance, obesity, Type 2 diabetes and metabolic syndrome, such as doxorubicin, Taxol, platinum-based drugs, aromatase inhibitors, gonadotropin-releasing hormone agonist as well as newer targeted therapies, such as thePI3K inhibitor Piqray® (alpelisib, Novartis),mTOR inhibitorsandsteroidsamong others. What is emerging is an understanding that these treatment-induced metabolic complications blunt the impact of the anti-cancer treatment itself and can evencause treatment resistance. Hyperglycemia and the subsequent hyperinsulinemia are common in cancer treatment. Yet, insulin levels, which are highly stimulative to many cancers, are rarely monitored and therefore rarely treated. It’s an oversight in clinical practice that needs to be remedied urgently.
LL: How can metabolic dysfunction and cancer growth be counteracted pharmacologically?
JS:At the moment, there are no drugs for targeting tumors sensitive to metabolic hormones. This is the gap in cancer treatment we are targeting with our leaddrug SDX-7320. As a stopgap, many oncologists give their patients metformin, as it hasbeen shown tohave a modest effect on cancer treatment-induced metabolic dysfunction and may even improve cancer outcomes. Occasionally, oncologists refer their cancer patients to endocrinologists for more acute metabolic care via anti-diabetic drugs like SGLT2 inhibitors. While these anti-diabetics may have clinical utility in helping control hyperglycemia, they generally haveonly a modest effect on hyperinsulinemia/insulin resistanceorhigh circulating leptin levels. As difficult as they are to maintain,diet and exerciseare still the best weapons in the battle against cancer treatment-induced metabolic dysfunction.
LL: Can you tell us more about the company’s lead compound SDX-7320, in terms of its design, mechanism of action, the indications it is being investigated for and the clinical programs currently underway?
JS:SynDevRx’s lead compound is SDX-7320 – a polymer-drug conjugate consisting of a small molecule MetAP2 inhibitor attached via a peptide linker to a high molecular weight polymer backbone. SDX-7320 is itself inert, butin vivo, the pharmacologically active small molecule fumagillol-derivative is released from the polymer/peptide linker upon contact with lysosomal enzymes. The concept behind the drug’s design was to improve the safety profile of the active small molecule by preventing it from crossing the blood–brain barrier –a known and challenging side effect of MetAP2 inhibitors. Another objective of the polymer-conjugation approach was to improve its drug-like properties, as fumagillin is unstable and poorly soluble.
The active small molecule is based on fumagillin, a natural product isolated from the fungusAspergillus fumigatusFresenius.Fumagillin and its derivatives are potent and selective inhibitors of the enzyme, MetAP2. Covalent modification of MetAP2 by the fumagillin pharmacophore not only inhibits the aminopeptidase activity of MetAP2, butalso results indecreased turnover and thus the accumulation of the inhibited protein. This results in multiple beneficial downstream effects including cell cycle arrest,modified angiogenic growth factors,improvements to the tumor immune micro-environmentandamelioration of dysregulated metabolic hormones.The polymer conjugation technology yields a number of advantages of SDX-7320 over traditional small molecule fumagillin-based MetAP2 inhibitors, for example dramatically superior water solubility, excellent stability, and a highly favorable PK profile which allows for a patient-friendly dosing schedule and administration by subcutaneous injection – a first for a polymer-drug conjugate. Additionally, the high average molecular weight of SDX-7320 has proven effective at minimizing the historic, class-specific CNS adverse effect observed with small-molecule fumagillin analogs.
Interestingly, our expectations for the polymer-drug conjugate were that we would see absolute doses increase significantly, with respect to the small molecule doses. Decades of polymer-drug conjugationresearchsuggested doses should increase by as much as 10x (compared to the small molecule) with little to no change in safety. In fact, we saw the opposite. In multiple head-to-head experiments, we saw greater activity with lower doses of the conjugate (in absolute drug weight terms) compared to the small molecule and with a better safety profile.
SDX-7320 is being developed for the treatment of cancers that are sensitive to metabolic hormones, with our first indication being breast cancer. APhase 1 trialof SDX-7320 was completed in 2020, in patients with advanced solid tumors. The results of this trial defined the recommended Phase 2 dose and schedule as well as demonstrated favorable effects on metabolic and angiogenic biomarkers. Clinical trials are planned in combination with standards of care in triple-negative breast cancer (TNBC) as well as in ER+/Her2- breast cancer in combination with a PI3K inhibitor (Piqray/alpelisib) in patients with aPIK3CAmutation.
Jim Shanahan was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.
