Commentary - Journal of Cellular Immunology (2020) Volume 2, Issue 2
Targeting Mesothelin in Pancreatic Ductal Adeno- Carcinoma PDAC
Christopher Montemagno1,2*, Gilles Pagès1,2
1Centre Scientifique de Monaco, Biomedical Department, 8 Quai Antoine Ier, MC-98000 Monaco, Principality of Monaco
2University Côte d’Azur, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284; INSERM U1081, Centre Antoine
Lacassagne, 06200 Nice, France
- *Corresponding Author:
- Christopher Montemagno
Received date: February 12, 2020; Accepted date: March 02, 2020
Citation: Montemagno C, Pagès G. Targeting Mesothelin in Pancreatic Ductal Adeno-Carcinoma (PDAC). J Cell Immunol. 2020;
Copyright: © 2020 Montemagno C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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
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.
- Kleeff J, Korc M, Apte M, La Vecchia C, Johnson
CD, Biankin AV, Neale RE, Tempero M, Tuveson DA,
Hruban RH, Neoptolemos JP. Pancreatic cancer. Nature
reviews Disease primers. 2016 Apr 21;2(1):1-22.
- 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.
- 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.
- Aslan M, Shahbazi R, Ulubayram K, Ozpolat B.
Targeted therapies for pancreatic cancer and hurdles
ahead. Anticancer research. 2018 Dec 1;38(12):6591-
- Ryan DP, Hong TS, Bardeesy N. Pancreatic
adenocarcinoma. New England Journal of Medicine.
2014 Sep 11;371(11):1039-49.
- 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.
- Hassan R, Ho M. Mesothelin targeted cancer
immunotherapy. European journal of cancer. 2008 Jan
- 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
- Morello A, Sadelain M, Adusumilli PS. Mesothelintargeted
CARs: driving T cells to solid tumors. Cancer
discovery. 2016 Feb 1;6(2):133-46.
- 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.
- 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.
- 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.
- Debie P, Devoogdt N, Hernot S. Targeted nanobodybased
molecular tracers for nuclear imaging and imageguided
surgery. Antibodies. 2019 Mar;8(1):12.
- 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
- 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.
- 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.
- 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
- 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.