Theratechnologies Inc T.TH

RE:AACR - late breaking absracts text posted by noon today

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Presenter/Authors

Cyndia Charfi1, Michel Demeule1, Jean-Christophe Currie1, Alain Zgheib2, Bogdan Alexandru Danalache2, Richard Bliveau2, Christian Marsolais1, Borhane Annabi1

1Theratechnologies, Montreal, QC, Canada,2Universit du Qubec Montral, Montreal, QC, Canada

Disclosures

 C. Charfi,
Theratechnologies Employment, Stock, Stock Option, Patent.
M. Demeule,
Theratechnologies Employment, Stock, Stock Option, Patent.
J. Currie,
Theratechnologies Employment, Stock, Stock Option, Patent.
A. Zgheib,
Theratechnologies Stock, Patent.
B. Alexandru Danalache, None. 
R. Bliveau,
Theratechnologies Stock, Stock Option, Grant/Contract, Patent.
C. Marsolais,
Theratechnologies Employment, Stock, Stock Option, Patent.
B. Annabi,
Theratechnologies Stock, Stock Option, Grant/Contract, Patent.

Abstract

Over the last decade, the targeting of specific cell surface receptors such as human epidermal growth factor receptor 2 (Her2) in breast cancer cells has allowed the emergence of innovative strategies for the delivery of anticancer agents. High expression levels of the sortilin receptor (SORT1) have been reported in various tumors of breast cancer patients, including triple-negative breast cancer (TNBC), HR+ and Her2+ breast cancers. Given SORT1 function in ligand internalization, we addressed the sorting and trafficking of the newly designed TH19P01 peptide recognizing SORT1, and of TH1902, an anticancer TH19P01-docetaxel conjugate (PDC), and whether such PDC could target SORT1+ breast cancers. In vitro, high expression of SORT1 was found in several TNBC and Her2+ breast cancer cell lines as well as in in more than 88% of cases (H-score >100) from commercial breast cancer tissue microarrays. SORT1-mediated cell surface binding and internalization of TH19P01 was first investigated in TNBC-derived MDA-MB-231 cells. The binding and uptake of Alexa488-labeled TH19P01, at 4 and 37°C respectively, were found significantly reduced upon siRNA-mediated SORT1 silencing. This demonstrates that functional SORT1 processes are required for both cell surface recognition and internalization of TH19P01. Moreover, the internalization of TH19P01 and TH1902 in MDA-MB-231 cells were monitored by fluorescence microscopy using a polyclonal antibody generated against TH19P01. Both TH19P01 and TH1902 showed a rapid uptake and co-localized in the perinuclear region with the late endosomal marker Rab-7 and with the lysosomal marker Lamp-1 within 30 minutes indicating that both compounds are internalized through a receptor-mediated endocytosis pathway. In addition, TH19P01 internalization after 1 hour appeared significantly associated within intracellular compartments of MDA-MB-231 cells whereas Herceptin remained mostly localized at the cell surface of Her2+ BT-474 cells. In vivo, weekly administration of intravenous bolus of TH1902 (35 mg/kg) at an equivalent docetaxel MTD dose (15 mg/kg) led to complete tumor regression, while docetaxel only inhibited tumor growth by half in a murine MDA-MB-231 xenograft tumor model. Furthermore, in mice bearing Her2+ HCC-1954 breast tumor xenografts, TH1902 induced complete tumor regression in contrast to docetaxel and Herceptin. Taken together, these preclinical data demonstrate the high anticancer properties of TH1902 against SORT1+ TNBC and Herceptin resistant Her2+ breast cancers. These results demonstrate that TH1902 can be a promising avenue for personalized therapy in the treatment of all SORT1+ breast cancers.