Investigators Seek Simpler Solution to Treatment Resistance in Esophageal Cancer

More than 20,000 adults in the United States are diagnosed with esophageal cancer every year.¹ Although the incidence, location, and histology of esophageal cancer vary globally, patients in the Western World typically develop esophageal cancer in the distal esophagus or at the gastroesophageal junction (Figure 1).¹ The most common disease type is esophageal adenocarcinoma (EAC), which may point to obesity as a factor.

Rising obesity rates across the United States have led to increasing reflux disease, Barrett esophagus, and esophageal adenocarcinoma.^2-4 Overall survival for esophageal cancer remains poor, especially for metastatic disease with a median survival of slightly over 1 year from the time of diagnosis.⁵ Metastatic EAC is typically managed with chemotherapy and immunotherapy, but many patients eventually develop resistance to these therapies, leading to poor outcomes.

Exploring and targeting the underlying mechanisms of therapeutic resistance are critical for improving the outlook for esophageal cancer. Therefore, it is of utmost importance to identify new treatment options or repurpose commonly used drugs in novel combinations to improve outcomes in this difficult-to-treat patient population.

Targeting the Role of Stress in Therapeutic Resistance

Study results have recently discovered that adrenergic stress hormones produced during the fight-or-flight response are key players in psychological stress, such as anxiety or depression, which are significantly increased following a cancer diagnosis. Our team at Roswell Park Comprehensive Cancer Center in Buffalo, New York, led by Elizabeth Repasky, PhD, discovered that stress can reduce the efficacy of chemotherapy and the immune system’s power to control tumor growth.^6,7 Interestingly, our work has also revealed a solution to this problem.

Propranolol, a type of beta-blocker, is commonly prescribed for heart problems such as hypertension or arrhythmia and management of anxiety and migraines. Propranolol blocks the β-adrenergic receptors by which stress hormones act on both tumors and immune cells. Using propranolol in mice enhances long-term immune control of tumor growth by reducing the accumulation of myeloid-derived suppressor cells.⁸ Moreover, the resistance to cytotoxic chemotherapy caused by stress can be reversed by using propranolol.⁹ The same phenomenon might be possible in humans.

A team of researchers at Roswell Park Comprehensive Cancer Center, led by Anurag Singh, MD, showed that patients undergoing chemoradiation for esophageal cancer who took β-blockers for high blood pressure did better than those patients not taking β-blockers.¹⁰ Our previous clinical trial in advanced melanoma patients, led by Shipra Gandhi, MD, showed that combining immunotherapy (pembrolizumab [Keytruda]) with propranolol produces an unprecedented response rate, one not seen historically with immunotherapy alone without significantly increased adverse effects (AEs).¹¹ Therefore, we hypothesize that adding propranolol to standard chemotherapy and immunotherapy for esophageal cancer will significantly improve outcomes and not cause additional AEs.

A New Use for an Existing Drug?

Based on these premises, our team at Roswell Park is conducting a multicenter, nonrandomized, single-arm, phase 2 clinical trial (NCT05651594). Patients with advanced or metastatic EAC will be treated with a combination of standard chemotherapy-immunotherapy and propranolol (Figure 2).¹²

We aim to enroll a total of 40 patients over 2 years, with at least 20 patients enrolled at our site. The study’s primary end point is the overall response rate (ORR) as determined by RECIST 1.1 criteria. Secondary end points include safety (toxicities and AEs) assessed as per Common Terminology Criteria for Adverse Events Version 5.0, progression-free survival, overall survival, and ORR as determined by immune-based RECIST criteria. The correlative studies will analyze blood- and tissue-based biomarkers, including immune markers. Perceived stress and the chronotropic effect of exercise will be correlated with clinical outcomes to determine the efficacy of the study treatment combination.

Survival with standard chemotherapy- immunotherapy for esophageal cancer remains very poor. Propranolol is affordable and very well tolerated. If the study results are favorable, propranolol could be quickly and widely implemented in clinical practice.

Sarbajit Mukherjee, MD, MS, is an assistant professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

References

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6. Eng JWL, Reed CB, Kokolus KM, et al. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through beta-adrenergic receptor activation. Nat Commun. 2015;6:6426. doi:10.1038/ncomms7426
7. Mohammadpour H, MacDonald CR, Qiao G, et al. β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J Clin Invest. 2019;129(12):5537-5552. doi:10.1172/JCI129502
8. MacDonald C, Ministero S, Pandey M, et al. Comparing thermal stress reduction strategies that influence MDSC accumulation in tumor bearing mice. Cell Immunol. 2021;361:104285. doi:10.1016/j. cellimm.2021.104285
9. Hylander BL, Eng JWL, Repasky EA. The impact of housing temperature-induced chronic stress on preclinical mouse tumor models and therapeutic responses: an important role for the nervous system. Adv Exp Med Biol. 2017;1036:173-189. doi:10.1007/978-3-319-67577-0_12
10. Farrugia MK, Ma SJ, Mattson DM, Flaherty L, Repasky EA, Singh AK. Concurrent β-blocker use is associated with improved outcome in esophageal cancer patients who undergo chemoradiation: a retrospective matched-pair analysis. Am J Clin Oncol. 2020;43(12):889894. doi:10.1097/COC.0000000000000768
11. Gandhi S, Pandey MR, Attwood K, et al. Phase I clinical trial of combination propranolol and pembrolizumab in locally advanced and metastatic melanoma: safety, tolerability, and preliminary evidence of antitumor activity. Clin Cancer Res. 2021;27(1):87-95. doi:10.1158/1078-0432.CCR-20-2381
12. Propranolol in combination with pembrolizumab and standard chemotherapy for the treatment of unresectable locally advanced or metastatic esophageal or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov. Updated December 19, 2022. Accessed January 3, 2022. https://clinicaltrials.gov/ct2/show/NCT05651594