Activity of nab-sirolimus alone or in combination with cabozantinib, octreotide, or talazoparib in nonclinical neuroendocrine tumor models

Scott Paulson; Michael J. Demeure; Allen L. Cohn; Alexandria T. Phan; Maria Zalath; Jr. Edward C. Spindler,; Shihe Hou

doi:10.1530/endoabs.108.B19

B19

Prev Next

Section Contents Cite

Endocrine Abstracts (2024) 108 B19 | DOI: 10.1530/endoabs.108.B19

NANETS2024 17th Annual Multidisciplinary NET Medical Symposium NANETS 2024 Applied Basic Science (13 abstracts)

Activity of nab-sirolimus alone or in combination with cabozantinib, octreotide, or talazoparib in nonclinical neuroendocrine tumor models

Scott Paulson ¹ , Michael J. Demeure ^2,3 , Allen L. Cohn ⁴ , Alexandria T. Phan ⁵ , Maria Zalath ⁶ , Edward C. Spindler , Jr. ⁶ & Shihe Hou ⁶

Author affiliations

¹Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas, TX; ²Hoag Memorial Hospital Presbyterian, Newport Beach, CA; ³Translational Genomics Research Institute, Phoenix, AZ; ⁴Rocky Mountain Cancer Center, Denver, CO; ⁵Cancer Center–Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI; ⁶Aadi Bioscience, Morristown, NJ

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is strongly implicated in the pathogenesis and progression of neuroendocrine tumors (NETs). nab-Sirolimus, an injectable form of albumin-bound sirolimus, demonstrates greater tumor drug accumulation, mTOR target inhibition, and antitumor activity in human tumor models compared to conventional mTOR inhibitors including everolimus. This study utilized NET cell lines for in vitro and in vivo evaluation of the anti-proliferative and antitumor activity of nab-sirolimus as a single agent or in combination with targeted agents with known activity in NETs.

Methods: In vitro cell viability assays evaluated the anti-proliferative effect of nab-sirolimus (20 or 80 nM) alone or in combination with clinically relevant concentrations (0.037 to 80 µM) of talazoparib, octreotide, or cabozantinib in 3 different NET cell lines: BON-1 (human pancreatic), NCI-H209 (human small cell lung carcinoma), and STC-1 (murine gastrointestinal). BON-1 was subsequently selected for in vivo evaluation. Athymic nude mice (n = 8 per group) bearing subcutaneous (SC) BON-1 xenografts were treated with either saline, or clinically equivalent relevant doses of nab-sirolimus, cabozantinib, octreotide, or talazoparib alone or in combination for 6 weeks to assess antitumor activity (Table).

Results: In vitro, nab-sirolimus showed anti-proliferative effects as a single agent across all 3 NET cell lines and additive effects were observed in combination with talazoparib and cabozantinib. In BON-1 xenografts, nab-sirolimus demonstrated greater antitumor activity compared to other single agent treatments, and significant additive effects were observed when nab-sirolimus was combined with cabozantinib, octreotide, or talazoparib (Table).

Table 1. Antitumor Activity of nab-Sirolimus Alone or in Combination in BON-1 Xenografts
Treatment	TGI^a (P-value)^b
nab-Sirolimus 5 mg/kg, IV weekly	77%
Cabozantinib-5 5 mg/kg, PO daily	44% (0.0019)
Cabozantinib-15 15 mg/kg, PO daily	66% (0.2646)
Octreotide 0.1 mg/kg, SC daily	12% (0.0012)
Talazoparib 0.33 mg/kg, PO daily	35% (0.0371)
nab-Sirolimus+Cabozantinib-5	86% (0.0002)
nab-Sirolimus+Cabozantinib-15	89% (0.0290)
nab-Sirolimus+Octreotide	81% (0.0006)
nab-Sirolimus+Talazoparib	90% (0.0075)
IV=intravenous; PO=oral; TGI=tumor growth inhibition.^aTGI is percent versus saline on Day 33.^bP-value (ANOVA) for single agents=comparison with nab-sirolimus;P-value for combinations=comparison with non-nab-sirolimus component.

Conclusions: Single agent nab-sirolimus showed significant in vitro and in vivo activity in NET lines. Combinations of nab-sirolimus with other targeted agents demonstrated additive anti-proliferative and antitumor activity; however, the magnitude of response for select combinations compared with single agent activity warrants further investigation.

ABSTRACT ID28547