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10.3390/cancers12030757
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Article

LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications

by
Eytan Ben-Ami
1,
Raul Perret
2,
Ying Huang
1,
Félicie Courgeon
3,4,
Prafulla C. Gokhale
1,
Audrey Laroche-Clary
3,4,
Benjamin K. Eschle
1,
Valérie Velasco
2,
François Le Loarer
2,
Marie-Paule Algeo
5,
James Purcell
6,
George D. Demetri
1,7,† and
Antoine Italiano
3,4,5,*,†
1
Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
2
Department of Pathology, Institut Bergonié, 33000 Bordeaux, France
3
Sarcoma Unit, Institut Bergonié, 33000 Bordeaux, France
4
INSERMU1218, 33000 Bordeaux, France
5
University of Bordeaux, 33400 Talence, France
6
AbbVie Biotherapeutics, Redwood City, CA 94063, USA
7
Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02215, USA
*
Author to whom correspondence should be addressed.
†
These two authors contributed equally to the work.
Cancers 2020, 12(3), 757; https://doi.org/10.3390/cancers12030757
Submission received: 2 February 2020 / Revised: 12 March 2020 / Accepted: 17 March 2020 / Published: 23 March 2020
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Abstract

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies.
Keywords: LRRC15; sarcoma; ABBV-085 LRRC15; sarcoma; ABBV-085

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MDPI and ACS Style

Ben-Ami, E.; Perret, R.; Huang, Y.; Courgeon, F.; Gokhale, P.C.; Laroche-Clary, A.; Eschle, B.K.; Velasco, V.; Le Loarer, F.; Algeo, M.-P.; et al. LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications. Cancers 2020, 12, 757. https://doi.org/10.3390/cancers12030757

AMA Style

Ben-Ami E, Perret R, Huang Y, Courgeon F, Gokhale PC, Laroche-Clary A, Eschle BK, Velasco V, Le Loarer F, Algeo M-P, et al. LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications. Cancers. 2020; 12(3):757. https://doi.org/10.3390/cancers12030757

Chicago/Turabian Style

Ben-Ami, Eytan, Raul Perret, Ying Huang, Félicie Courgeon, Prafulla C. Gokhale, Audrey Laroche-Clary, Benjamin K. Eschle, Valérie Velasco, François Le Loarer, Marie-Paule Algeo, and et al. 2020. "LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications" Cancers 12, no. 3: 757. https://doi.org/10.3390/cancers12030757

APA Style

Ben-Ami, E., Perret, R., Huang, Y., Courgeon, F., Gokhale, P. C., Laroche-Clary, A., Eschle, B. K., Velasco, V., Le Loarer, F., Algeo, M.-P., Purcell, J., Demetri, G. D., & Italiano, A. (2020). LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications. Cancers, 12(3), 757. https://doi.org/10.3390/cancers12030757

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