Theranostic Profiling for Actionable Aberrations in Advanced High Risk Osteosarcoma with Aggressive Biology Reveals High Molecular Diversity: The Human Fingerprint Hypothesis

Abstract

The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3.Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis.

Keywords: Bone tumors; CLIA; Next generation sequencing; Osteosarcoma; Sarcoma; Targeted therapy; biomarker.

Figure 1. Morphoproteomic analysis of mTOR expression:

First figure (patient 8) shows activation of mTOR pathway in all tumor cells as evidenced by phosphorylation of mTOR at serine 2448, at an intensity of 1-2+, occasionally nuclear, but mostly plasmalemmal and cytoplasmic. Second figure (patient 10) shows activation of the mTOR pathway in a minor component of the tumor cells with both nuclear and cytoplasmic-plasmalemmal expression of pMTOR (Ser 2448). This indicates both mTORC2 and mTORC1 activation, but again only in a minor component of the tumor