Inhibiting TGF-β to increase response rates to chemoradiotherapy in rectal cancer

Abstract

With the rapid increase in the incidence of rectal cancer in young adults, 1 Bailey CE Hu CY You YN et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975–2010. JAMA Surg. 2015; 150: 17-22 Crossref PubMed Scopus (528) Google Scholar interest in organ preservation as an oncologically safe 2 Garcia-Aguilar J Patil S Gollub MJ et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022; (published online April 28.)https://doi.org/10.1200/JCO.22.00032 Crossref PubMed Scopus (28) Google Scholar , 3 Smith JJ Strombom P Chow OS et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol. 2019; 5: e185896 Crossref PubMed Scopus (208) Google Scholar and cost-effective strategy to improve patients' quality of life has also been growing. 4 Miller JA Wang H Chang DT Pollom EL Cost-effectiveness and quality-adjusted survival of watch and wait after complete response to chemoradiotherapy for rectal cancer. J Natl Cancer Inst. 2020; 112: 792-801 Crossref PubMed Scopus (12) Google Scholar Studies evaluating novel radiosensitisers in rectal cancer are receiving attention as a consequence of the need to develop personalised treatment strategies to increase response rates while also facilitating organ preservation. The TGF-β pathway has intrigued scientists and clinicians for decades, 5 Barnard JA Beauchamp RD Coffey RJ Moses HL Regulation of intestinal epithelial cell growth by transforming growth factor type beta. Proc Natl Acad Sci USA. 1989; 86: 1578-1582 Crossref PubMed Scopus (316) Google Scholar and targeting this complex signalling network has now been implicated as a potential way to improve response to radiotherapy. 6 Batlle E Massagué J Transforming growth factor-β signaling in immunity and cancer. Immunity. 2019; 50: 924-940 Summary Full Text Full Text PDF PubMed Scopus (781) Google Scholar However, decades of research into TGF-β inhibitors—both as a monotherapy and in combination with radiotherapy—have shown mixed clinical efficacy, probably due to the complex biology of TGF-β and the context-dependent effects of its inhibition. 6 Batlle E Massagué J Transforming growth factor-β signaling in immunity and cancer. Immunity. 2019; 50: 924-940 Summary Full Text Full Text PDF PubMed Scopus (781) Google Scholar , 7 Andarawewa KL Paupert J Pal A Barcellos-Hoff MH New rationales for using TGFbeta inhibitors in radiotherapy. Int J Radiat Biol. 2007; 83: 803-811 Crossref PubMed Scopus (58) Google Scholar Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trialThe addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. Full-Text PDF