Genomics, Morphoproteomics, and Treatment Patterns of Patients with ASPS
Posted: Sun May 03, 2020 5:03 pm
Roman Groisberg, Jason Roszik, Anthony P. Conley, et al.
Mol Cancer Ther Published OnlineFirst March 3, 2020.
Abstract
Overexpression of transcription factor 3 in alveolar soft part
sarcoma(ASPS) results in upregulation of cell proliferation pathways.
No standard treatment algorithm exists for ASPS; multikinase
inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint
inhibitors (ICI) have shown clinical benefit. To date, no studies have
reported on management strategies or sequencing of therapy. We
evaluated ASPS treatment patterns and responses in an experimental
therapeutics clinic. Genomic and morphoproteomic analysis was
performed to further elucidate novel targets. We retrospectively
reviewed patients with ASPS treated on clinical trials. Demographic
and clinical next-generation sequencing (NGS) profiles were collected.
AACR GENIE database was queried to further evaluate
aberrations in ASPS. Morphoproteomic analysis was carried out to
better define the biology of ASPS with integration of genomic and
proteomic findings. Eleven patients with ASPS were identified; 7
received NGS testing and mutations in CDKN2A (n ¼ 1) and
hepatocyte growth factor (n ¼ 1) were present. Ten patients were
treated with TKIs with stable disease as best response and 4 patients
with ICI (three partial responses). Within GENIE, 20 patients were
identified harboring 3 called pathogenic mutations. Tumor mutation
burden was low in all samples. Morphoproteomic analysis
confirmed the expression of phosphorylated c-Met. In addition,
fatty acid synthase and phosphorylated-STAT3 were detected in
tumor cell cytoplasm and nuclei. Patients with ASPS have a
quiescent genome and derive clinical benefit from VEGFtargeting
TKIs. Morphoproteomic analysis has provided both
additional correlative pathways and angiogenic mechanisms that
are targetable for patients with ASPS. Our study suggests that
sequential therapy with TKIs and immune checkpoint inhibitors
is a reasonable management strategy.
Mol Cancer Ther Published OnlineFirst March 3, 2020.
Abstract
Overexpression of transcription factor 3 in alveolar soft part
sarcoma(ASPS) results in upregulation of cell proliferation pathways.
No standard treatment algorithm exists for ASPS; multikinase
inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint
inhibitors (ICI) have shown clinical benefit. To date, no studies have
reported on management strategies or sequencing of therapy. We
evaluated ASPS treatment patterns and responses in an experimental
therapeutics clinic. Genomic and morphoproteomic analysis was
performed to further elucidate novel targets. We retrospectively
reviewed patients with ASPS treated on clinical trials. Demographic
and clinical next-generation sequencing (NGS) profiles were collected.
AACR GENIE database was queried to further evaluate
aberrations in ASPS. Morphoproteomic analysis was carried out to
better define the biology of ASPS with integration of genomic and
proteomic findings. Eleven patients with ASPS were identified; 7
received NGS testing and mutations in CDKN2A (n ¼ 1) and
hepatocyte growth factor (n ¼ 1) were present. Ten patients were
treated with TKIs with stable disease as best response and 4 patients
with ICI (three partial responses). Within GENIE, 20 patients were
identified harboring 3 called pathogenic mutations. Tumor mutation
burden was low in all samples. Morphoproteomic analysis
confirmed the expression of phosphorylated c-Met. In addition,
fatty acid synthase and phosphorylated-STAT3 were detected in
tumor cell cytoplasm and nuclei. Patients with ASPS have a
quiescent genome and derive clinical benefit from VEGFtargeting
TKIs. Morphoproteomic analysis has provided both
additional correlative pathways and angiogenic mechanisms that
are targetable for patients with ASPS. Our study suggests that
sequential therapy with TKIs and immune checkpoint inhibitors
is a reasonable management strategy.