Mesothelin as a Relevant Tumor Imaging and Therapeutic Target in Pancreatic Ductal Adeno-Carcinoma
Pancreatic Ductal Adenocarcinoma (PDAC) represents 90% of all pancreatic malignancies . To date, PDAC is the fourth leading cause of cancer-related death and its incidence is rising to become the second one in the next decade . Two major public health problems, obesity and type 2 diabetes, are important etiology factors involved in PDAC development . Despite intense research efforts, PDAC is an aggressive tumor with a five-year survival rate of 5% . The reasons for this dramatic prognosis are multiple; 1) PDAC are often resistant to chemo and or radiotherapy ; 2) 90% of PDAC are diagnosed at advanced stages, limiting therapeutic windows ; 3) most of the clinical trials investigating targeted therapies alone failed to demonstrate improvement of patients overall survival .
Identification of PDAC antigens for diagnosis and therapy is an urgent need to improve patient management. Relevant targets have been identified and included mesothelin. Mesothelin is a membrane-associated glycoprotein with limited expression in normal tissues including mesothelial cells of the pleura, pericardium and peritoneum . Mesothelin is overexpressed in several solid tumors and accumulating evidences suggest its role as a diagnostic marker and as a relevant therapeutic target in ovarian cancer, mesothelioma and PDAC. Mesothelin expression has been reported in 80 to 85 % of PDAC . A weak expression of mesothelin in normal tissues and an overexpression in cancer tissues make mesothelin an attractive target for therapy. Several antibodies-based compounds targeting mesothelin and immunotherapies are under clinical investigations in several tumors [8,9]. However, the selection of patients eligible to these therapies needs a companion test detecting mesothelin expression.
In the October 2019 issue of Cancers (Basel), we presented results from TCGA datasets . Based on 179 PDAC patient samples, we showed a restricted expression of mesothelin in tumor specimens as compared to healthy pancreatic tissues. These results were recently confirmed by immunohistochemical analysis of PDAC samples and their healthy counterparts . We further showed that high mesothelin expression was correlated with shorter overall survival. Moreover, an elevated expression in advanced stages of PDAC was observed suggesting a role of mesothelin in tumor progression. Consistently, the role of mesothelin in peritoneal metastasis of PDAC through an induction of angiogenesis was recently suggested .
We next investigated the potential of 99mTc-A1, a radiolabeled single-domain antibody (sdAb)-derived imaging agent, as a mesothelin-targeting probe . This class of imaging agents specifically binds their target at early time point after injection, with elevated tumor-tobackground ratio . Currently, mesothelin-targeting agents are monoclonal antibodies (mAbs) or single-chain variable fragments (scFv) [14-16]. Although antibodies have been extensively considered for in vivo imaging, their slow blood clearance and their high non-specific background restricted their use. The smaller size of sdAb-derived imaging agents allows fast blood clearance and high target-to-background ratio at early time point. In this study, 99mTc-A1 showed a non-invasive imaging of mesothelin-expressing PDAC, with elevated tumorto- background ratio 1h post-injection. No signal was observed on SPECT images after 99mTc-A1 injection with the exception of tumor, kidney and bladder. Renal accumulation was observed in agreement with the general pattern of sdAb distribution .
Future directions of this work will include clinical translation of 99mTc-A1 as a companion marker to identify patients that should benefit of anti-mesothelin therapies. This theranostic approach will open new opportunities for the management of cancer patients. The incorporation of high-energy β- ( 177Lu) to anti-mesothelin sdAb will specifically kills mesothelin-expressing tumor cells.
This theranostic methodology will couple a molecular imaging to (i) predict response to the targeted radionuclide therapy and (ii) to follow up treatment efficacy. Radiolabeling with an imaging-dedicated radioisotopes (such as 68Ga) or with a therapy-dedicated one (such as 177Lu) can be performed with the same sdAb. This method has been successfully performed in preclinical model of breast cancer without any evidence of renal damage . A better management of PDAC patients is also expected. Further development will therefore include DOTA- chelation chemistry to allow either 68Ga or 177Lu radiolabeling for diagnosis and therapy of PDAC.
Combining a therapeutic agent to a specific method of detection of aggressive tumor is the future of precision medicine.
This work was supported by the Fondation de France.
2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer research. 2014 Jun 1;74(11):2913-21.
3. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. New England Journal of Medicine. 2003 Apr 24;348(17):1625-38.
4. Aslan M, Shahbazi R, Ulubayram K, Ozpolat B. Targeted therapies for pancreatic cancer and hurdles ahead. Anticancer research. 2018 Dec 1;38(12):6591- 606.
5. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. New England Journal of Medicine. 2014 Sep 11;371(11):1039-49.
6. Nichetti F, Marra A, Corti F, Guidi A, Raimondi A, Prinzi N, de Braud F, Pusceddu S. The role of mesothelin as a diagnostic and therapeutic target in pancreatic ductal adenocarcinoma: a comprehensive review. Targeted oncology. 2018 Jun 1;13(3):333-51.
7. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. European journal of cancer. 2008 Jan 1;44(1):46-53.
8. Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I. Mesothelin immunotherapy for cancer: ready for prime time?. Journal of Clinical Oncology. 2016 Dec 1;34(34):4171.
9. Morello A, Sadelain M, Adusumilli PS. Mesothelintargeted CARs: driving T cells to solid tumors. Cancer discovery. 2016 Feb 1;6(2):133-46.
10. Montemagno C, Cassim S, Trichanh D, Savary C, Pouyssegur J, Fagret D, Broisat A, Ghezzi C. 99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin- Expressing Pancreatic Ductal Adenocarcinoma. Cancers. 2019 Oct;11(10):1531.
11. Le K, Wang J, Zhang T, Guo Y, Chang H, Wang S, Zhu B, Park HJ, Piao L, Seo EH, Lee SH. Overexpression of Mesothelin in Pancreatic Ductal Adenocarcinoma (PDAC). Int J Med Sci. 2020;17(4):422-7.
12. Avula LR, Rudloff M, El-Behaedi S, Arons D, Albalawy R, Chen X, Zhang X, Alewine C. Mesothelin enhances tumor vascularity in newly forming pancreatic peritoneal metastases. Molecular Cancer Research. 2020 Feb 1;18(2):229-39.
13. Debie P, Devoogdt N, Hernot S. Targeted nanobodybased molecular tracers for nuclear imaging and imageguided surgery. Antibodies. 2019 Mar;8(1):12.
14. ter Weele EJ, van Scheltinga AG, Kosterink JG, Pot L, Vedelaar SR, Lamberts LE, Williams SP, Lubde Hooge MN, de Vries EG. Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts. Oncotarget. 2015 Dec 8;6(39):42081.
15. Yakushiji H, Kobayashi K, Takenaka F, Kishi Y, Shinohara M, Akehi M, Sasaki T, Ohno E, Matsuura E. Novel single-chain variant of antibody against mesothelin established by phage library. Cancer science. 2019 Sep;110(9):2722-33.
16. Kobayashi K, Sasaki T, Takenaka F, Yakushiji H, Fujii Y, Kishi Y, Kita S, Shen L, Kumon H, Matsuura E. A novel PET imaging using 64Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells. Journal of immunology research. 2015;2015.
17. Tchouate Gainkam LO, Caveliers V, Devoogdt N, Vanhove C, Xavier C, Boerman O, Muyldermans S, Bossuyt A, Lahoutte T. Localization, mechanism and reduction of renal retention of technetium - 99m labeled epidermal growth factor receptor - specific nanobody in mice. Contrast media & molecular imaging. 2011 Mar;6(2):85-92.
18. D’huyvetter M, Vincke C, Xavier C, Aerts A, Impens N, Baatout S, De Raeve H, Muyldermans S, Caveliers V, Devoogdt N, Lahoutte T. Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody. Theranostics. 2014;4(7):708.