Spinal Metastases and the Evolving Role of Molecular Targeted Therapy, Chemotherapy, and Immunotherapy

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved; however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved responses compared to standard chemotherapy. We present clinical examples of excellent responses in spinal metastatic disease which have not been specifically documented in the literature, as most clinical trials evaluate treatment response based on visceral disease. This review is useful for the spine surgeons treating patients with metastatic disease as knowledge of these responses could help with timing and planning of surgical interventions, as well as promote multidisciplinary discussions, allowing development of an individualized treatment strategy to patients presenting with widespread multifocal progressive disease, where surgery could lead to suboptimal results

Recruited Cells Can Become Transformed and Overtake PDGF-Induced Murine Gliomas In Vivo during Tumor Progression

Gliomas are thought to form by clonal expansion from a single cell-of-origin, and progression-associated mutations to occur in its progeny cells. Glioma progression is associated with elevated growth factor signaling and loss of function of tumor suppressors Ink4a, Arf and Pten. Yet, gliomas are cellularly heterogeneous; they recruit and trap normal cells during infiltration.We performed lineage tracing in a retrovirally mediated, molecularly and histologically accurate mouse model of hPDGFb-driven gliomagenesis. We were able to distinguish cells in the tumor that were derived from the cell-of-origin from those that were not. Phenotypic, tumorigenic and expression analyses were performed on both populations of these cells. Here we show that during progression of hPDGFb-induced murine gliomas, tumor suppressor loss can expand the recruited cell population not derived from the cell-of-origin within glioma microenvironment to dominate regions of the tumor, with essentially no contribution from the progeny of glioma cell-of-origin. Moreover, the recruited cells can give rise to gliomas upon transplantation and passaging, acquire polysomal expression profiles and genetic aberrations typically present in glioma cells rather than normal progenitors, aid progeny cells in glioma initiation upon transplantation, and become independent of PDGFR signaling.These results indicate that non-cell-of-origin derived cells within glioma environment in the mouse can be corrupted to become bona fide tumor, and deviate from the generally established view of gliomagenesis

Dual activating FGFR1

Abstract Background Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic region, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates. Pilomyxoid astrocytoma management remains controversial, with pathologic tissue diagnosis and relief of mass effect being the main goals of surgery while avoiding treatment‐related morbidity, including vision loss, panhypopituitarism, and hypothalamic dysfunction. Chemotherapy (typically vincristine and carboplatin) in all pediatric patients and radiation therapy in pediatric patients over 5 years of age are used for treatment. Methods We report clinical presentation, surgical management, and whole exome sequencing results in a pediatric patient with the subtotally resected pilomyxoid astrocytoma. Results We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has been described as a gatekeeper mutation imparting resistance to FGFR inhibitors. Interestingly, both mutations were present with similar variant allele frequency within the tumor. Conclusion Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma

PDGF+Cre vs. PDGF only tumors; genes with >2-fold downregulated TE and FDR<0.05.

<p>PDGF+Cre vs. PDGF only tumors; genes with >2-fold downregulated TE and FDR<0.05.</p

<i>In vivo</i> quantification of ribosome-bound and total RNA levels revealed a broad range of ribosome recruitment efficiencies amongst mRNA transcripts.

<p>(A) Distribution of mRNA expression in ribosome-bound and total RNA pools from PDGF-driven glioma identified differential TE (N = 4). (B) TE values for each biological replicate (black points) plotted with the average of the other three replicates (red line) demonstrated reproducibility of measurements. (C) Signal-to-noise ratios of TE measurements (blue bars) identified range of high confidence measurements relative to a normal distribution (red line). (D) GSEA identified statistical overrepresentation of defined gene ontologies amongst efficiently and inefficiently translated genes. Black bars represent distribution of mRNAs from indicated geneset amongst all genes ranked by signal to noise ratio (top panel). Red line represents GSEA output enrichment score. R = Pearson correlation coefficient.</p

GBM is a heterogeneous tumor composed of multiple cell types, including both tumor and stromal cells.

<p>(A) Immunohistochemical staining of mouse PDGF-driven glioma identified multiple tumor regions composed of different cell types. (B) PDGF-HA oncogene expressed from tumor cells colocalized with Olig2 staining by IHC. (C) FACS analysis of tumors generated in Olig2-eGFPL10a mice with PDGF-RFP bicistronic retrovirus identified tumor cells as Olig2+. Scale bar, 100 µm.</p

Translation efficiency was altered in glioma compared to normal brain OPCs.

<p>(A) Changes in ribosome-bound mRNA correlated somewhat with changes in total cellular RNA between tumor and normal brain OPCs (N = 4). (B) Alterations in TE between tumor and normal brain were reproducible, exceeding average replicate error. (C) Genesets associated with cell division and biosynthetic pathways predominated amongst GOSlim Biological Process genesets most enriched for transcripts translationally upregulated in Olig2+tumor cells compared to normal brain OPCs. Enrichment plots for chromosome organization and mitosis genesets shown. (D) Genesets associated with synaptic signaling predominated amongst GO Biological Process genesets most enriched for transcripts translationally downregulated in Olig2+tumor cells compared to normal brain OPCs. Enrichment plots for transmission of nerve impulse and synaptic transmission shown. NES = Normalized Enrichment Score. R = Pearson correlation coefficient.</p

PTEN loss altered the translation state of glioma cells.

<p>(A) TE measurements of PTEN WT and PTEN deleted tumors were very similar (N = 4). (B) Changes in both total RNA and TE contributed to alteration in ribosome-bound RNA caused by PTEN loss. (C) GO genesets associated with oxidative phosphorylation were amongst those most enriched for transcripts translationally downregulated in PTEN-deleted vs PTEN WT tumors. Enrichment plots for electron transport chain and cellular respiration genesets shown. (D) Genesets associated with glycolysis predominated amongst GO genesets most enriched for transcripts translationally upregulated in PTEN-deleted vs PTEN WT tumors. Enrichment plots shown for genesets for hydrolase activity acting on glycosyl bonds and transferase activity transferring glycosyl bonds. NES = Normalized Enrichment Score. R = Pearson correlation coefficient.</p