IL-13Rα2-Targeted Therapy Escapees: Biologic and Therapeutic Implications

Abstract INTRODUCTION 77Lu-DOTATATE, a radionuclide therapy which binds SST2A, has demonstrated efficacy in neuroendocrine tumors and evidence of CNS penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. METHODS SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by two experienced pathologists (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (< 10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (range=0-12). RESULTS A total of 117 tumor samples from 113 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean±SD=7.6±3.6 [n=36]) and meningioma (5.7±3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3±0.6 [n=3]), ETMR (1.0±0 [n=3]), ependymoma (grades I-III; 0.2±0.7 [n=26]), and high-grade glioma (grades III-IV; 0.4±0.7 [n=22]). Pineoblastoma (3.8±1.5 [n=4]) and other embryonal tumors (2.3±3.8 [n=8]) exhibited intermediate, variable expression. Among expressors, there was no association between SST2A IHC score and patient age, sex, presence of metastases, likelihood of relapse, or prior treatment. In a subset of paired primary and recurrent specimens from 3 patients, SST2A IHC scores remained largely unchanged. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.6±3.2) than SHH (5.0±3.3) molecular subgroups (p=0.033). CONCLUSIONS High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

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Comprehensive genomic profiling (CGP) of esophageal and tubular GI tumors to identify frequencies of ErbB family member amplification with therapeutic implications.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.8 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 8-8

Author(s):

Mark Bailey ◽

Siraj Mahamed Ali ◽

Alexa Betzig Schrock ◽

Samuel Jacob Klempner ◽

Ben George ◽

...

Keyword(s):

Targeted Therapy ◽

Family Member ◽

Gastroesophageal Junction ◽

Acquired Resistance ◽

Response To Treatment ◽

Genomic Alteration ◽

Erbb Family ◽

Therapeutic Implications ◽

Clinical Support ◽

Comprehensive Genomic Profiling

8 Background: As described in the MyPathway study, amplification and other mutations in ErbB-family proteins are actionable events across solid tumors. Targeting ERBB2 amplifications (amp) in tubular GI cancers (TGC) improves patient outcomes. ErbB family comparisons across anatomic sites is lacking and here we describe the largest known series in TGC. Methods: DNA was extracted from 12,685 FFPE clinical TGC specimens, including 1,720 esophageal CA*. CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of 720X for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: Across all TGC cases, amp was the most frequent genomic alteration among ErbB members at 8.7%. ERBB2 amp was 2.3x as common as EGFR amp across TGC. Across TGC sites, EGFR amp was most frequent in esophageal SCC (13.7%) and ERBB2 amp was most common in gastroesophageal junction adenoCA (21%) compared with overall frequencies of 2.7% and 5.5% respectively. ERBB3 and ERBB4 amp were rare, and most common in gastroesophageal adenoCA relative to other TGC. Clinical support with outcomes for patients treated with anti-ErbB targeted therapy across TGC will be presented, including profiling from cases of acquired resistance to anti-ErbB targeted therapy. Conclusions: Among TGC, esophageal CA harbored the most ErbB family member amp with variation by histology. Profiling across ErbB proteins in TGC suggests biologic differences and may affect response to treatment. CGP can expand the population who may benefit from anti-ErbB directed therapies and refine treatment choices. Further research is warranted. [Table: see text]

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Targeted Therapy Resistance Mechanisms and Therapeutic Implications in Melanoma

Hematology/Oncology Clinics of North America ◽

10.1016/j.hoc.2014.03.001 ◽

2014 ◽

Vol 28 (3) ◽

pp. 523-536 ◽

Cited By ~ 18

Author(s):

Guo Chen ◽

Michael A. Davies

Keyword(s):

Targeted Therapy ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Therapeutic Implications

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A Pancancer Analysis of the Expression Landscape and Clinical Relevance of Fibroblast Growth Factor Receptor 2 in Human Cancers

Frontiers in Oncology ◽

10.3389/fonc.2021.644854 ◽

2021 ◽

Vol 11 ◽

Author(s):

Juanni Li ◽

Kuan Hu ◽

Jinzhou Huang ◽

Lei Zhou ◽

Yuanliang Yan ◽

...

Keyword(s):

Targeted Therapy ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor Receptor ◽

Therapeutic Targets ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Genetic Aberrations ◽

Therapeutic Implications ◽

Clinical Associations

Background: Fibroblast growth factor receptor 2 (FGFR2) is frequently altered in tumors and one of the top therapeutic targets in cholangiocarcinoma (CHOL) with FGFR2 fusions. Although there have been several studies on individual tumors, a comprehensive analysis of FGFR2 genetic aberrations and their simultaneous clinical implications across different tumors have not been reported.Methods: In this study, we used the large comprehensive datasets available, covering over 10,000 tumor samples across more than 30 cancer types, to analyze FGFR2 abnormal expression, methylation, alteration (mutations/fusions and amplification/deletion), and their clinical associations.Results: Alteration frequency, mutation location distribution, oncogenic effects, and therapeutic implications varied among different cancers. The overall mutation rate of FGFR2 is low in pancancer. CHOL had the highest mutation frequency, and fusion accounted for the major proportion. All these fusion aberrations in CHOL were targetable, and an FDA-approved drug was approved recently. Uterine corpus endometrial carcinoma (UCEC) had the highest number of FGFR2 mutations, and the most frequently mutated positions were S252W and N549K, where the functional impact was oncogenic, but targeted therapy was less effective. Additionally, DNA methylation was associated with FGFR2 expression in several cancers. Moreover, FGFG2 expression and genetic aberrations showed clinical associations with patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets.Conclusions: This study showed the full FGFR2 alteration spectrum and provided a broad molecular perspective of FGFR2 in a comprehensive manner, suggesting some new directions for clinical targeted therapy of cancers.

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The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

Medical Oncology ◽

10.1007/s12032-019-1329-2 ◽

2019 ◽

Vol 37 (1) ◽

Cited By ~ 20

Author(s):

Ryota Tamura ◽

Toshihide Tanaka ◽

Yasuharu Akasaki ◽

Yuichi Murayama ◽

Kazunari Yoshida ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Targeted Therapy ◽

Growth Factor ◽

Tumor Microenvironment ◽

Immune Checkpoint ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Therapeutic Implications ◽

Immunosuppressive Cells ◽

Endothelial Growth Factor

Abstract The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological “cold tumors” into the “hot tumors”. Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.

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Approach to Oligometastatic Prostate Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_159241 ◽

2016 ◽

pp. 119-129 ◽

Cited By ~ 2

Author(s):

Brandon Bernard ◽

Boris Gershman ◽

R. Jeffrey Karnes ◽

Christopher J. Sweeney ◽

Neha Vapiwala

Keyword(s):

Prostate Cancer ◽

Targeted Therapy ◽

Systemic Therapy ◽

De Novo ◽

Locally Advanced ◽

Specific Antigen ◽

Clinical State ◽

Therapeutic Implications ◽

Oligometastatic Prostate Cancer ◽

Disease Free

Oligometastatic prostate cancer has increasingly been recognized as a unique clinical state with therapeutic implications. It has been proposed that patients with oligometastases may have a more indolent course and that outcome may be further improved with metastasis-directed local ablative therapy. In addition, there are differing schools of thoughts regarding whether oligometastases represent isolated lesions—where targeted therapy may render a patient disease free—or whether they coexist with micrometastases, where targeted therapy in addition to systemic therapy is required for maximal clinical impact. As such, the approach to the patient with oligometastatic prostate cancer requires multidisciplinary consideration, with surgery, radiotherapy, and systemic therapy potentially of benefit either singularly or in combination. Indeed, mounting evidence suggests durable disease-free intervals and, in some cases, possibly cure, may be achieved with such a multimodal strategy. However, selecting patients that may benefit most from treatment of oligometastases is an ongoing challenge. Moreover, with the advent of new, highly sensitive imaging technologies, the spectrum based on CT of the abdomen and pelvis and technetium bone scan of localized to oligometastatic to widespread disease has become increasingly blurred. As such, new MRI- and PET-based modalities require validation. As some clinical guidelines advise against routine prostate-specific antigen screening, the possibility of more men presenting with locally advanced or de novo oligometastatic prostate cancer exists; thus, knowing how best to treat these patients may become more relevant at a population level. Ultimately, the arrival of prospective clinical data and better understanding of biology will hopefully further inform how best to treat men with this disease.

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Therapeutic target expression in advanced prostate cancer patients submitted for comprehensive molecular profiling.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15209 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15209-e15209

Author(s):

Brian Wright ◽

Matthew Jerome McGinniss ◽

Anatole Ghazalpour ◽

Christopher Roberts ◽

Ryan P Bender ◽

...

Keyword(s):

Targeted Therapy ◽

Potential Benefit ◽

Tumor Tissue ◽

Molecular Level ◽

High Potential ◽

Negative Potential ◽

Molecular Profile ◽

Wild Type ◽

Therapeutic Implications ◽

Clinical Strategies

e15209 Background: Approximately 30,000 men die from advanced PCa annually. The prognosis of this disease stresses a need for novel therapeutic and clinical strategies. Methods: We analyzed targeted genes and proteins in 141 patient specimens using IHC (for as many as 29 different biomarkers), FISH for EGFR, ALK, c-Myc, Her2neu and TOP2A, sequencing for BRAF, c-ckit, EGFR, KRAS, and PIK3CA, and RNA expression microarray. Therapeutic associations from the published literature were then assigned based on the differentially expressed biomarkers. Due to amount of tumor tissue present in the specimen, physician test requests and other factors, the number of biomarkers interrogated varied from case to case. Results: Therapeutic associations based on IHC results included:) 92% HER2 negative (potential lack of benefit from HER2 targeted therapy); 85% AR high (potential benefit from anti-androgen therapy); 79% ERCC1 negative (potential benefit from platinum-based therapies); 70% TS negative (potential benefit from fluorouracil),54% PTEN negative (suggesting activation of PIK3CA pathway), 66% RRM1 low (potential benefit from gemcitabine); 64% TOPO2A low (potential lack of benefit from anthracyclines); 44% TOPO1 high (potential benefit from irinotecan) 34% MGMT high (potential lack of benefit from temozolomide); 28% SPARC high (potential benefit from nab-paclitaxel). Potential therapeutic associations based on FISH and Sequencing included: 82% HER2 negative by FISH (potential minimal benefit to HER2 targeted therapy), 13% EGFR positive by FISH and a majority 90% and 81% wild-type for KRAS (exons 2, 3) and BRAF (exons 11, 15), respectively, indicating potential benefit from EGFR targeted therapies. Interestingly, two drug pumps, PGP and MRP1 were 85% negative and 91% positive, respectively. Conclusions: Advanced PCa is an aggressive disease where a one-size-fit-all approach is not effective. Our data confirms that these tumors are heterogeneous at the molecular level and has important therapeutic implications. When developing biomarker enriched clinical trials or advanced treatment planning, a comprehensive molecular profile may provide important insights not otherwise considered.

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