ALK-targeted therapy for poor-prognosis childhood cancers

Background: This study aims to investigate the correlation of VEGF-B and FLT-1 co-expression with the prognosis of gastric cancer (GC). Materials & methods: Primary GC samples and adjacent tissues were obtained from 96 patients. Results: Both VEGF-B and FLT-1 were testified to be upregulated in the human GC compared with adjacent tissues. Spearman’s rank correlation analysis indicated that VEGF-B and FLT-1 expression were correlated (r = 0.321, p = 0.0015). High VEGF-B and FLT-1 co-expression patients showed poor prognosis when compared with low VEGF-B and FLT-1 co-expression patients (p = 0.0169). Conclusion: The high co-expression of VEGF-B and FLT-1 in GC shows a poor prognosis of overall survival, and targeted therapy against the interaction between VEGF-B and FLT-1 is worth further detailed analysis.

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Cancer-associated fibroblasts of colorectal cancer and their markers: updates, challenges and translational outlook

Future Oncology ◽

10.2217/fon-2020-0384 ◽

2020 ◽

Vol 16 (29) ◽

pp. 2329-2344 ◽

Cited By ~ 1

Author(s):

Marahaini Musa ◽

Adli Ali

Keyword(s):

Colorectal Cancer ◽

Targeted Therapy ◽

Poor Prognosis ◽

Mortality Rates ◽

Colorectal Carcinogenesis ◽

Detection Methods ◽

Cancer Associated Fibroblasts ◽

Marker Detection ◽

Efficient Screening ◽

Marker Identification

Accumulation of cancer-associated fibroblasts (CAFs) in the tumor microenvironment is associated with poor prognosis and recurrence of colorectal cancer (CRC). Despite their prominent roles in colorectal carcinogenesis, there is a lack of robust and specific markers to classify the heterogeneous and highly complex CAF populations. This has resulted in confusing and misleading definitions of CAFs in cancer niche. Advancements in molecular biology approaches have open doors to reliable CAF marker detection methods in various solid tumors. These discoveries would contribute to more efficient screening, monitoring and targeted therapy of CRC thus potentially will reduce cancer morbidity and mortality rates. This review highlights current scenarios, dilemma, translational potentials of CAF biomarker and future therapeutic applications involving CAF marker identification in CRC.

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Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5003 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5003-5003

Author(s):

Kim N. Chi ◽

Sinja Taavitsainen ◽

Nayyer Iqbal ◽

Cristiano Ferrario ◽

Michael Ong ◽

...

Keyword(s):

Targeted Therapy ◽

Clinical Benefit ◽

Poor Prognosis ◽

Objective Response ◽

Progression Free Survival ◽

Pi3k Pathway ◽

Primary Objective ◽

Therapy Outcomes ◽

Prognostic Criteria ◽

Clinical Benefit Rate

5003 Background: The treatment for poor prognosis mCRPC includes taxanes and androgen receptor (AR) targeted therapy, however the optimal treatment is undefined. Methods: Patients (pts) with poor prognosis (liver metastases, early CRPC ( < 12 months from ADT start), and/or > 3 of 6 poor prognostic criteria (Chi et al, Annals of Oncol, 2016)) were randomized to receive CAB (Arm A) or AR targeted therapy (Arm B, ABI or ENZ by investigator choice) with cross over at progression. Primary objective was to determine the clinical benefit rate (CBR) (PSA decline ≥50% (PSA50), objective response (OR), or stable disease (SD) ≥ 12 weeks). Plasma was sampled serially for circulating tumour DNA (ctDNA). Results: 95 pts were randomized (Arm A: 45, Arm B: 50): 18% had liver mets, 88% early CRPC and 30% had > 3 of 6 poor prognostic criteria. 52% of pts had prior docetaxel, half for castration sensitive disease. Table summarizes 1st-line therapy outcomes. Baseline ctDNA fraction > 15% (median) was associated with shorter 1st-line progression-free survival (PFS) (median 2.8 vs 8.4 m, HR = 2.54, P < 0.001) and overall survival (OS) (median 14.0 vs 38.7 m, HR = 2.64, P = 0.001). ctDNA alterations in AR, TP53, PI3K pathway, RB1 and DNA repair were detected in 53%, 45%, 31%, 23%, and 21% of pts. Shorter PFS and OS were associated with AR gain (HR 2.57 (95% CI 1.63-4.06); HR 3.59, (1.9-6.69), respectively) and TP53 defects (HR 2.62 (CI 1.65-4.15); HR 3.33 (CI 1.8-6.14), respectively). Pts with concurrent defects in TP53 and RB1 had a trend for worse PFS/OS than pts with TP53 defect alone. AR rearrangements predicted to disrupt the ligand binding domain were detected in 6% of pts and had a shorter PFS (HR = 2.60 (1.11 - 6.09)) with a trend for shorter OS (HR = 2.27 (0.89 - 5.81)). Conclusions: In this poor prognosis cohort, 1st-line treatment with CAB had a higher clinical benefit rate than treatment with ABI/ENZA. Elevated ctDNA and genomic alterations in AR and TP53 were prognostic. Supported in part by Sanofi. Clinical trial information: NCT02254785. [Table: see text]

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Abstract A41: TRICEPS: A feasibility study of personalized targeted therapy in relapsed/refractory childhood cancers

10.1158/1538-7445.pedca15-a41 ◽

2016 ◽

Author(s):

Sylvie Langlois ◽

Jasmine Healy ◽

Mathieu Lajoie ◽

Sophie Dumoucel ◽

Fida Khater ◽

...

Keyword(s):

Targeted Therapy ◽

Feasibility Study ◽

Childhood Cancers

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Outcomes of patients (pts) with renal cell carcinoma and sarcomatoid dedifferentiation (sRCC) treated with nephrectomy (Nx) and systemic therapies (T) over three decades: The MD Anderson Cancer Center (MDACC) experience.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.534 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 534-534

Author(s):

Sarp K. Keskin ◽

Pavlos Msaouel ◽

Kenneth R. Hess ◽

Surena F. Matin ◽

Eric Jonasch ◽

...

Keyword(s):

Targeted Therapy ◽

Primary Tumor ◽

Poor Prognosis ◽

Cox Regression ◽

Clear Cell ◽

Rank Test ◽

Cancer Center ◽

Significant Difference ◽

Systemic Therapies

534 Background: Pts with sRCC historically have had a poor prognosis. We determined the overall survival (OS) and prognostic factors of pts treated with Nx and T in the cytokine and targeted therapy eras. Methods: This is a retrospective study of pts with sRCC who had Nx and received T at MDACC in the cytokine era (1987-2005) or the targeted therapy era (2006-2015). OS was measured from time of diagnosis until death of any cause or last follow-up. OS times were estimated by Kaplan-Meier plots and were compared using the log-rank test. Cox regression models were used to determine the association of covariables with OS. Results: Among 199 pts with sRCC (80.9% clear-cell) identified, 167 pts (83.9%) have died at a median follow-up of 8.8 years (median OS 16.5 months; 95% CI: 15.2, 20.9). The 1-year, 2-year, and 5-year OS rates were 67%, 38%, and 14%, respectively. There was no significant difference in OS between pts with clear-cell vs. those with non-clear cell histology. Pts with metastatic disease at initial diagnosis had a significantly shorter OS compared with pts with localized disease (median 12.1 months vs. 23.3 months; p=0.0064). Biopsy of the primary tumor or a metastatic site was able to detect the presence of sarcomatoid features in only 7% of cases. The % of sarcomatoid component (<10%, 10-40%, >40%) in the primary tumor did not impact OS. For first-line (1L) therapy, 77 pts (39%) received targeted agents, and 122 pts (61%) received chemotherapy or cytokines. Although a significant improvement in OS rate was observed at 1 year for pts treated in the targeted therapy era (p = 0.011), this effect was attenuated at year 2 and disappeared at years 3-5 after diagnosis. Conclusions: Pts with sRCC still have poor prognosis with no clear long-term benefit of targeted therapy, underscoring the need to develop more effective systemic therapies for these patients.

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Molecularly guided treatment of metastatic parotid gland carcinoma in adults

Wiener klinische Wochenschrift ◽

10.1007/s00508-020-01778-8 ◽

2020 ◽

Author(s):

Hossein Taghizadeh ◽

Leonhard Müllauer ◽

Robert M. Mader ◽

Thorsten Füreder ◽

Gerald W. Prager

Keyword(s):

Targeted Therapy ◽

Parotid Gland ◽

Poor Prognosis ◽

Treatment Approach ◽

Molecular Profiling ◽

Disease Entity ◽

Advanced Therapy ◽

Therapy Recommendation ◽

Gland Carcinoma ◽

Parotid Gland Carcinoma

Summary Background Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. Methods In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. Results We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. Conclusion A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

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Decreased Expression of PACSIN1 in Brain Glioma Samples Predicts Poor Prognosis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.696072 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhou Zimu ◽

Zhang Jia ◽

Fu Xian ◽

Ma Rui ◽

Ren Yuting ◽

...

Keyword(s):

Targeted Therapy ◽

Poor Prognosis ◽

Molecular Subtype ◽

Neurological Diseases ◽

Postoperative Radiotherapy ◽

Clinical Indicators ◽

Kinase Substrate ◽

Functional Annotations ◽

Tissue Specimens ◽

Brain Gliomas

Gliomas are the most severe brain tumours with a poor prognosis. Although surgery, postoperative radiotherapy and chemotherapy can improve the survival rate of glioma patients, the prognosis of most glioma patients is still poor. In recent years, the influence of gene-targeted therapy on gliomas has been gradually discovered, and intervening the occurrence and development of brain gliomas from the perspective of the gene will significantly improve treatment prognosis. Protein Kinase C and Casein Kinase Substrate in Neurons 1 (PACSIN1) is a member of the conserved peripheral membrane protein family in eukaryotes. Improper expression of PACSIN1 can lead to neurological diseases such as Huntington’s disease and schizophrenia. However, its relationship with tumours or even gliomas has not been explored. The study aims to explore PACSIN1 as a prognostic factor that can predict overall survival (OS) for gliomas. We collected the data from CGGA, TCGA, GEO databases and the pathological glioma tissue specimens from 15 clinical glioma patients surgically resected. The differential expression of PACSIN1 in various clinical indicators, the genes related to PACSIN1 expression, the prognostic value of PACSIN1 and the functional annotations and pathway analysis of differently expressed genes (DEGs) were analysed. The results revealed that PACSIN1 had low expression levels in grade IV, IDH1 wild-type and 1p/19q non-codel group gliomas, and PACSIN1 was considered a mesenchymal molecular subtype marker. PACSIN1 expression is positively correlated with OS in all gliomas and it was found that PACSIN1 influenced the occurrence and development of gliomas through synaptic transmission. The PACSIN1 expression is negatively correlated with the malignant degree of gliomas and positively associated with the OS, indicating that PACSIN1 would play an essential role in the occurrence and development of gliomas and might be a potential new biomarker and targeted therapy site for gliomas.

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Fusion Oncoproteins in Childhood Cancers: Potential Role in Targeted Therapy

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-26.6.541 ◽

2021 ◽

Vol 26 (6) ◽

pp. 541-555

Author(s):

Sara D. A. Angione ◽

Alemayehu Y. Akalu ◽

Jessica Gartrell ◽

Elimika Pfuma Fletcher ◽

Gilbert J. Burckart ◽

...

Keyword(s):

Targeted Therapy ◽

Molecular Genetics ◽

Cause Of Death ◽

Scientific Knowledge ◽

Targeted Therapies ◽

Potential Role ◽

Chromosomal Rearrangements ◽

Childhood Cancers ◽

Pediatric Cancers ◽

Pediatric Sarcomas

Cancer remains the leading cause of death from disease in children. Historically, in contrast to their adult counterparts, the causes of pediatric malignancies have remained largely unknown, with most pediatric cancers displaying low mutational burdens. Research related to molecular genetics in pediatric cancers is advancing our understanding of potential drivers of tumorigenesis and opening new opportunities for targeted therapies. One such area is fusion oncoproteins, which are a product of chromosomal rearrangements resulting in the fusion of different genes. They have been identified as oncogenic drivers in several sarcomas and leukemias. Continued advancement in the understanding of the biology of fusion oncoproteins will contribute to the discovery and development of new therapies for childhood cancers. Here we review the current scientific knowledge on fusion oncoproteins, focusing on pediatric sarcomas and hematologic cancers, and highlight the challenges and current efforts in developing drugs to target fusion oncoproteins.

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EGFR and HER2 small molecules inhibitors as potential therapeutics in veterinary oncology

Revista Colombiana de Ciencias Químico Farmacéuticas ◽

10.15446/rcciquifa.v49n2.89898 ◽

2020 ◽

Vol 49 (2) ◽

Author(s):

Juan Martín Cadena García ◽

Carlos Eduardo Giraldo Murillo ◽

Manuela Ramos Jaramillo

Keyword(s):

Targeted Therapy ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Small Molecules ◽

Poor Prognosis ◽

Kinase Inhibitor ◽

Human Cancer ◽

High Morbidity ◽

Her2 Expression ◽

Potential Therapeutics

EGFR and HER2 receptors are crucial signaling molecules tyrosine kinase involved in human cancer. Aberrant signaling is associated with a variety of cancers, frequently with poor prognosis. Currently, EGFR and HER2 receptors are being targeted by small molecules, which offer a huge benefit to those patients afflicted by aggressive forms of cancer, improving their prognosis. Both human and canine cancers share molecular, biological, histopathological and clinical similarities, including EGFR and HER2 expression in some forms of cancer. However, despite the use of one tyrosine kinase inhibitor approved to treat canine mastocytoma, canine cancers overexpressed EGFR and HER2 do not yet have targeted therapy, leading to high morbidity and mortality. Targeting EGFR and HER2 receptors in canine cancers using comparative approaches in human cancer could lead to better outcomes.

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Acute perimyocarditis with cardiac tamponade in COVID-19 infection without respiratory disease

BMJ Case Reports ◽

10.1136/bcr-2020-236218 ◽

2020 ◽

Vol 13 (8) ◽

pp. e236218

Author(s):

Havard Dalen ◽

Espen Holte ◽

Anna Ulstein Guldal ◽

Johan-Arnt Hegvik ◽

Knut Haakon Stensaeth ◽

...

Keyword(s):

Intensive Care ◽

Targeted Therapy ◽

Cardiac Tamponade ◽

Respiratory Disease ◽

Poor Prognosis ◽

Troponin T ◽

Cardiac Injury ◽

Cardiac Biomarkers ◽

Haemodynamic Instability ◽

Cardiac Ultrasound

The COVID-19 pandemic with its severe respiratory disease has caused overflow to hospitals and intensive care units. Elevated troponins and natriuretic peptides are related to cardiac injury and poor prognosis. We present a young woman with COVID-19 infection with haemodynamic instability caused by acute perimyocarditis and cardiac tamponade. Troponin T was modestly elevated. Focused cardiac ultrasound made the diagnosis. Echocardiography revealed transient thickening of the myocardial walls. After pericardial drainage and supportive care, she improved significantly within 1 week without targeted therapy. The case illustrates the importance of cardiac diagnostic imaging in patients with COVID-19 and elevated cardiac biomarkers.

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