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. 2017 Nov 21;7(1):15963.
doi: 10.1038/s41598-017-13114-8.

Outcomes of patients with sarcoma enrolled in clinical trials of pazopanib combined with histone deacetylase, mTOR, Her2, or MEK inhibitors

Vikas Dembla  1 , Roman Groisberg  1 , Ken Hess  2 , Siqing Fu  1 , Jennifer Wheler  3 , David S Hong  1 , Filip Janku  1 , Ralph Zinner  4 , Sarina Anne Piha-Paul  1 , Vinod Ravi  5 , Robert S Benjamin  5 , Shreyaskumar Patel  5 , Neeta Somaiah  5 , Cynthia E Herzog  6 , Daniel D Karp  1 , Jason Roszik  7   8 , Funda Meric-Bernstam  1 , Vivek Subbiah  9
Affiliations

Outcomes of patients with sarcoma enrolled in clinical trials of pazopanib combined with histone deacetylase, mTOR, Her2, or MEK inhibitors

Vikas Dembla et al. Sci Rep. .

Abstract

Pazopanib is US FDA approved for the treatment of advanced soft tissue sarcomas. All patients with this disease ultimately develop resistance to therapy. Mechanisms of resistance include activation of the mTOR, histone deacetylase (HDAC), MAPK, and ERBB4 pathways. We hypothesized that combining pazopanib with other targeted agents inhibiting these pathways would increase response rates. We retrospectively evaluated the safety and efficacy of pazopanib plus vorinostat, everolimus, lapatinib or trastuzumab, and MEK inhibitor in patients with advanced sarcoma. The Cancer Geneome Atlas (TCGA) data was analyzed for HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations from sarcoma TCGA. Of the 44 advanced sarcoma patients in these trials, 27 (61%) were male; 18 (41%) had bone sarcoma, and 26 (59%) had soft tissue sarcoma. Best response was partial response (PR) in four patients [(overall response rate (ORR) = 9%, 95% confidence interval [CI] 3% to 22%)]. The median progression-free survival (PFS) for all patients was 9.6 weeks (95% CI 8.0 to 15.7 weeks). Analysis of TCGA data revealed HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations in 112/243 (46%) of patients predominantly HDAC1-11 (41%) alterations. Pazopanib combinations did demonstrate safety in combination with other agents. TCGA data suggests further evaluation of epigenetic pathway inhibitors in sarcoma.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Kaplan-Meier curves for PFS and OS.
Figure 2
Figure 2
PFS outcomes for patients with sarcoma.
Figure 3
Figure 3
OS by RMH prognostic score.
Figure 4
Figure 4
Pre- and post-treatment computed tomography scans of patients with sarcoma showing partial responses to pazopanib combinations. (A), (B) Alveolar soft part sarcoma before (A) and after (B) treatment, with 40% decrease in size of lung metastases (green arrow) per RECIST. (C,D) Angiosarcoma of the scalp metastatic to the lung before (C) and after (D) treatment, with 54% reduction in size of lung metastases per RECIST.
Figure 5
Figure 5
The Cancer Genome Atlas (TCGA) figure was generated to show copy number alterations, and mutations in selected genes namely HDAC, PI3K, HER2, and MAPK/RAS/RAF. The figure panel was created using the cBioPortal [ref: https://www.ncbi.nlm.nih.gov/pubmed/22588877] for the sarcoma data set available on the portal.
See this image and copyright information in PMC

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