24 Sep Bispecific Inhibitor Helps Overcome Pancreatic Cancer Drug Resistance
MedicalResearch.com Interview with:
Hadas Reuveni, PhD
VP of Research and Development
MedicalResearch.com: What is the background for this study?
Response: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide. Current treatments fail to provide patients with an effective and long-lasting response, mostly given to the nature of the tumor microenvironment which hinders drug accessibility, the late stage on diagnosis and the rapid upregulation of compensatory alternative signaling pathways by the tumor cells that lead to cancer drug resistance. Two of the major parallel pathways regulating tumor survival and metastasis as well as the crosstalk of the tumor and its microenvironment are mediated by insulin receptor substrate (IRS) 1 and 2, and by the signal transducer and activator of transcription 3 (STAT3). Both IRS1 and STAT3 have been shown to play a significant role in development of drug resistance by tumor cells.
NT219, the focus of the current study, is a small molecule that presents a new concept in cancer therapy. NT219 represents a new family of novel compounds acting as a dual inhibitor of both IRS1/2 and STAT3 signaling both directly in the tumor and its microenvironment. We have previously shown that simultaneous inhibition of these two pathways is crucial to overcome drug resistance, and to prolong the positive response of the anti-cancer activity of approved cancer drugs. NT219 targets IRS1/2 for degradation using a unique mechanism, supported by a feed-forward decrease in IRS gene expression. A long-term suppression of both IRS and STAT3 by NT-219 has been demonstrated in previous preclinical studies, which lasted days following removal of NT219 from the cancer cells, assuring a strong and prolonged anti-cancer activity. This study was designed to investigate the efficacy of NT219 at overcoming drug resistance to several approved oncology therapies using patient-derived xenograft (PDX) models of KRAS mutant pancreatic cancer, as well as to validate NT219’s mechanism of action and optimal dose regimen.
MedicalResearch.com: What are the main findings? Why is this compound unique?
Response: NT219, when administered in combination with approved oncology chemotherapy gemcitabine reversed pre-existing acquired resistance to gemcitabine in four out of four PDX models and led to a complete response in some of the animals. Additionally, NT219 reversed resistance of the PDX tumors to the targeted therapy trametinib, a MEK inhibitor, and folfirinox, a chemotherapy regimen, when given in combination with those agents.
Gene expression analysis of the pancreatic tumor also validated NT219’s mechanism of action. Following a single treatment of the mice with NT219 and gemcitabine, the expression of IRS1 in the tumor was reduced by an average of 80% compared to the control group. Similar reduction in expression was observed for STAT3-regulated genes, as well as Ki67, a proliferation marker, and other genes involved in cancer drug resistance.
The sequence of administration of the therapies had a remarkable impact on the efficacy of NT219 in reversing resistance, and a stronger response was observed when NT219 was given prior to gemcitabine. NT219 showed a dose-dependent therapeutic effect on tumor growth, and increased levels of NT219 were observed in both plasma and the tumors upon increasing the administered dose.
Overall, these findings demonstrate the great potential of NT219 as a dual inhibitor of two relevant tumor survival pathways. Concurrent blockage of IRS 1/2 and STAT3 signaling by NT219 has the potential to prevent resistance to multiple anti-cancer drugs, extend the duration of effective drug treatment and restore drug sensitivity in resistant tumors.
MedicalResearch.com: What should readers take away from your report?
Response: Our study demonstrates that both STAT3 and IRS play a critical role in KRAS-induced pancreatic tumorigenesis and drug resistance, and that NT219 acts to dually suppress both pathways. Considering its unique model mechanism of action and proven efficacy in preclinical studies as well as the ubiquitous role of IRS1/2 and STAT3 signaling in cancer drug resistance, NT219 in combination with approved oncology drugs has the potential to become an effective tumor-agnostic alternative to treat not only pancreatic cancer but a variety of other hard to treat cancers.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Given this positive preclinical data, additional studies should be performed to continue to advance NT219 as a valid and potential alternative for the treatment of pancreatic cancer patients. There are ongoing plans to study NT219 for the treatment of recurrent and metastatic squamous cell carcinoma of head and neck and in combination with cetuximab, an approved cancer drug with previously demonstrated synergy with NT219, and a Phase 1/2 clinical trial is expected to start next year.
MedicalResearch.com: Is there anything else you would like to add?
Response: Like pancreatic cancer patients, many other cancer patients are in desperate need of effective anti-cancer treatments that can prolong their survival to these devastating diseases. While novel immunotherapies and target cancer therapies have shown promising results, the percentage of patients responding to single-agent checkpoint inhibitor drugs is only 12.46% on average for all tumor types. In most cases, tumors acquire drug resistance and find a way to continue their growth. There is a great need for the development of combination therapies that can attack tumor cells from multiple angles to provide patients with long-lasting effective therapies.
NT219, A Novel Bi-specific Inhibitor of STAT3 and IRS1/2 Sensitized Resistant Pancreatic Tumors to Gemcitabine and MEK inhibitor and Induced Tumor Regression
AACR Pancreatic Cancer: Advances in Science and Clinical Care conference poster:
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