PDGFRA Research Articles

Unraveling Gastric and Small Intestine Gastrointestinal Stromal Tumors: A Review of Our Current Knowledge

Background: Gastrointestinal Stromal Tumors (GISTs) are characterized as round, well–defined mass lesions in the submucosal layer of the gastrointestinal (GI) tract. GISTs often present histological diversity and mutations in c-KIT and PDGFRA genes. Symptoms usually appear as abdominal pain, often accompanied by gastrointestinal bleeding or abdominal mass. The prognosis relies on tumor size, mitotic index, and different mutations, such as KIT mutations. There are a variety of diagnostic measures in the case of GISTs. However, it is important to note that ultrasound is the most common and reliable method for diagnosing gastric GISTs. The treatment methods followed vary from preoperative systemic therapy to surgical interventions. Depending on the type of GIST, professionals decide upon the best treatment plan for the patient. Objective: This review aims to inform the scientific community about the intricacies of gastric and small intestine GISTs to enhance understanding and improve patient management, with a particular focus on the importance of understanding and interpreting the unique microscopic histopathological findings of GISTs.

Protective effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.

Cellular senescence, characterized by a permanent state of cell cycle arrest and a secretory phenotype contributing to inflammation and tissue deterioration, has emerged as a target for age-related interventions. Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing. NP and AF cells demonstrated similar but distinct responses to the treatment. However, the effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to senescence associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-κB. Our findings reveal a novel anti-senescence role of PDGF in the IVD, demonstrating its ability to alleviate the senescent phenotype and protect against the progression of senescence. This makes it a promising candidate for preventing or treating IVD degeneration by targeting cellular senescence.

Clinicopathological and molecular genetic insights into EBV-positive inflammatory follicular dendritic cell sarcoma

Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell (FDC) sarcoma (EBV + IFDCS) is a rare entity, and its histopathological characteristics have not been fully described. This study aimed to investigate the clinical characteristics, pathological features, and molecular genetic profiles of EBV + IFDCS to improve our understanding of these lesions. A total of 12 EBV + IFDCS specimens were obtained from patients in our pathology diagnostic center. The clinical data, morphology, immunohistochemistry, in situ hybridization, and high-throughput DNA-targeted sequencing data were collected, and follow-up data were analyzed. These data were compared with those of 6 patients with traditional FDCS. The patients with EBV + IFDCS ranged from 21 to 84 years old, with a mean age of 52.3 years and a male-to-female ratio of 1:5. At the last follow-up, all patients were alive, with 2 experiencing recurrence and metastasis. In these cases, four were classified as the classical subtype, four as the angiomatoid/sclerosing subtype, and four as the lymphoma-like subtype, with two cases also exhibiting epithelioid granulomas. All patients exhibited heterogeneous expression of follicular dendritic cell markers (CD21, CD23, CD35, and CXCL13) alongside the fibroblast marker SMA, with significantly higher expressions of IgG4, EBER, and SMA in EBV + IFDCS patients compared to FDCS patients (P < 0.05). Conversely, SSTR2, EGFR, and STAT3 expression were significantly lower in the EBV + IFDCS group (P < 0.05). The average value of EBER was significantly higher in the classical subtype group (P = 0.022). Among the four cases of EBV + IFDCS analyzed for molecular genetic features, one patient exhibited germline mutations in the CDKN1C, PDGFRA, MSH2, FANCG, MLH1, ALK, and RUNX1 genes; three exhibited simultaneous SNP variations in the MTHFR gene; and two exhibited simultaneous SNP variations in the NQO1 gene. We conducted KEGG pathway analysis on the mutant genes, revealing significant enrichment in the cAMP signaling pathway, which plays a crucial role in tumor development. Survival analysis demonstrated that the median PFS rates were not reached (NR) for EBV + IFDCS patients, compared to 5 months (HR = 7.76) for FDCS patients. The 3-year PFS rates were 66.67% and 16.67%, respectively. Compared with the FDCS group, EBV + IFDCS patients had a significantly longer median PFS time (p < 0.05). In conclusion, EBV + IFDCS represents a group of tumors with unique clinical, morphological, immunological, prognostic, and molecular cytogenetic characteristics.

Knockout of histone deacetylase 8 gene in breast cancer cells may alter the expression pattern of the signaling molecules

Breast cancer (BC) is the most common cancer diagnosed in the world and it is also the main leading cause of cancer deaths in women. Change in epigenetic mechanisms promotes BC initiation and progression. Histone deacetylase 8 (HDAC8) was found to act as a potential oncogene in different malignancies. For better understanding of the HDAC8 function in BC development, we investigated the effect of HDAC8 deletion on the expression of genes involved in signaling pathways. In this study, CRISPR technology was used to knockout the HDAC8 gene in MDA-MB-468, MDA-MB-231 and MCF-7 cell lines. For this purpose, two gRNAs were designed and cloned into the PX459 vector. The gRNA-containing vectors were transfected into the BC cell lines and then the effect of this deletion on the expression of genes involved in signaling pathway was determined using quantitative real-time PCR (qRT-PCR). Analysis of qRT-PCR results showed a reduction in the expression of studied genes in BC cell lines after deletion of the HDAC8 gene compared to untreated controls. Although this decline was not significant for FGF2 and FGFR1 genes, however the mTOR, IGF1R, INSR, VEGFA and VEGFR2 genes showed statistically significant reduction in the studied BC cell lines. In addition, the down-regulation of PDGFC and PDGFRA genes were only significant in the TNBC cell lines. Overall, our study showed that HDAC8 can exert its oncogenic effects by altering the expression level of molecules involved in some signaling pathways, and inhibiting HDAC8 can revert these effects.

MicroRNA expression signature in gastrointestinal stromal tumour & their molecular & histological features.

Background & objectives In gastrointestinal stromal tumour (GIST), not only genetic abnormalities are responsible for adverse clinical events, but epigenetic modifications also play a crucial role. MicroRNA (miRNA) dysregulation plays a significant role in carcinogenesis as miRNAs serve as natural silencer for their targets. Our study aimed to explore the miRNAs expression and its association with molecular and histopathological characteristics of GIST. Methods Fifty GIST samples, including 45 formalin fixed paraffin embedded (FFPE) and fresh tissues were included. Peripheral non-tumour tissues were used as controls. All the cases were confirmed using immunohistochemistry. RNA was extracted using miRNA-specific kit, and the expression was performed using RT-qPCR. The data were evaluated using AriaMx software version 1.5 (Agilent, US). MiRNAs expression was analyzed by using the relative quantification method (ΔΔCT). Results miR-221, miR-222, miR-494 and miR-34a showed significant down-regulation in tumours relative to non-tumour tissues. The expression levels of these miRNAs were significantly down-regulated in c-KIT (proto-oncogene encoding the tyrosine kinase transmembrane receptor)-positive tumours compared to c-KIT-negative. Further analysis revealed that reduced expression was associated with spindle subtypes and gastric localization. However, there was no significant correlation with other histological features. Additionally, miR-221/222, and miR-494 were down-regulated in most of the KIT exon 11 mutant subtypes, while miRNA-34a was associated with platelet derived growth factor receptor alpha (PDGFRA) mutations. Interpretation & conclusions The present study showed that the down-regulation of these miRNAs may help better molecular classification and characterization of GISTs. Our results offer new insight into the association between miRNAs and histological features, enabling a more thorough understanding of GISTs at the molecular level.

Benchmarking of Approaches for Gene Copy-Number Variation Analysis and Its Utility for Genetic Aberration Detection in High-Grade Serous Ovarian Carcinomas.

Objective: The goal of this study was to compare the results of CNV detection by three different methods using 13 paired carcinoma samples, as well as to perform a statistical analysis of the agreement. Methods: CNV was studied using NanoString nCounter v2 Cancer CN Assay (Nanostring), Illumina Infinium CoreExome microarrays (CoreExome microarrays) and digital droplet PCR (ddPCR). Results: There was a good level of agreement (PABAK score > 0.6) between the CoreExome microarrays and the ddPCR results for finding CNVs. There was a moderate level of agreement (PABAK values ≈ 0.3-0.6) between the NanoString Assay results and microarrays or ddPCR. For 83 out of 87 target genes studied (95%), the agreement between the CoreExome microarrays and NanoString nCounter was characterized by PABAK values < 0.75, except for MAGI3, PDGFRA, NKX2-1 and KDR genes (>0.75). The MET, HMGA2, KDR, C8orf4, PAX9, CDK6, and CCND2 genes had the highest agreement among all three approaches. Conclusions: Therefore, to get a better idea of how to genotype an unknown CNV spectrum in tumor or normal tissue samples that are very different molecularly, it makes sense to use at least two CNV detection methods. One of them, like ddPCR, should be able to quantitatively confirm the results of the other.

Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle

AbstractAccumulation of senescent cells in tissues contributes to multiple aging-related pathologies. Senescent fibro-adipogenic progenitors (FAPs) contribute to aging-related muscle atrophy. Resistance training can help to maintain skeletal muscle mass, improve mobility, and reduce certain health risks commonly associated with aging. We investigated, using rat model, the impact of resistance training on FAPs in aging skeletal muscle, which remains unclear. Twenty-two-month-old female rats were divided into sedentary and training groups. The training group rodents were trained to climb a ladder while bearing a load for 20 training sessions over 2 months, after which, the flexor hallucis longus muscles were collected and analyzed. Senescent cells were identified using a senescence-associated β-galactosidase stain and p21 immunohistochemistry (IHC), and FAPs were identified using platelet-derived growth factor receptor alpha IHC. The results indicate that resistance training in rats prevented aging-associated skeletal muscle atrophy and suppressed M2 polarization of macrophages. The number of senescent cells was significantly reduced in the 24-month-old training group, with most of them being FAPs. Conversely, the number of senescent FAPs increased significantly in the 24-month-old sedentary group compared with that in the 18-month-old sedentary group. The number of senescent FAPs in the 24-month-old training group decreased significantly. Resistance training also suppressed the senescence-associated secretory phenotype (SASP). The killer T cell-specific marker, CD8α, was elevated in the skeletal muscles of the aging rats following resistance training, indicating upregulation of recognition and elimination of senescent cells. Overall, resistance training suppressed the accumulation of senescent FAPs and acquisition of SASP in aging skeletal muscles.

PDGFRα signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking.

Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) plays a critical role in craniofacial development, as mutations in PDGFRA are associated with cleft lip/palate in humans and Pdgfra mutant mouse models display varying degrees of facial clefting. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRα signaling during skeletal development in the mouse. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRα signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting, due to defects in proliferation and survival of cranial neural crest cells, and widespread alternative RNA splicing (AS) changes. Here, we sought to determine the molecular mechanisms by which Srsf3 activity is regulated downstream of PDGFRα signaling to control AS of transcripts necessary for craniofacial development. We demonstrated via enhanced UV-crosslinking and immunoprecipitation (eCLIP) of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. Moreover, we found that the subset of transcripts that are bound by Srsf3 and undergo AS upon PDGFRα signaling commonly encode regulators of PI3K signaling and early endosomal trafficking. Functional validation studies further confirmed that Srsf3 activity downstream of PDGFRα signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.

Brain and Serum Membrane Vesicle (Exosome) Profiles in Experimental Alcohol-Related Brain Degeneration: Forging the Path to Non-Invasive Liquid Biopsy Diagnostics

Background: Alcohol-related brain degeneration (ARBD) is associated with cognitive–motor impairments that can progress to disability and dementia. White matter (WM) is prominently targeted in ARBD due to chronic neurotoxic and degenerative effects on oligodendrocytes and myelin. Early detection and monitoring of WM pathology in ARBD could lead to therapeutic interventions. Objective: This study examines the potential utility of a non-invasive strategy for detecting WM ARBD using exosomes isolated from serum. Comparative analyses were made with paired tissue (Tx) and membrane vesicles (MVs) from the temporal lobe (TL). Methods: Long Evans rats were fed for 8 weeks with isocaloric liquid diets containing 37% or 0% caloric ethanol (n = 8/group). TL-Tx, TL-MVs, and serum exosomes (S-EVs) were used to examine ethanol’s effects on oligodendrocyte glycoprotein, astrocyte, and oxidative stress markers. Results: Ethanol significantly decreased the TL-Tx expression of platelet-derived growth factor receptor alpha (PDGFRA), 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), glial fibrillary acidic protein (GFAP), and 8-OHdG, whereas in the TL-MVs, ethanol increased CNPase, PDGFRA, and 8-OHdG, but decreased MOG and GFAP concordantly with TL-Tx. Ethanol modulated the S-EV expression by reducing PLP, nestin, GFAP, and 4-hydroxynonenal (HNE). Conclusion: Chronic ethanol exposures differentially alter the expression of oligodendrocyte/myelin, astrocyte, and oxidative stress markers in the brain, brain MVs, and S-EVs. However, directionally concordant effects across all three compartments were limited. Future studies should advance these efforts by characterizing the relationship between ABRD and molecular pathological changes in brain WM-specific exosomes in serum.

Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.

Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis. We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

Abdomen Malignant Myxoid Leiomyosarcoma with PDGFRA and TP53 Missense Mutation: A Case Report

Background: Malignant myxoid leiomyosarcoma (MMLS) is most commonly found in the uterus but can also occur in other areas, such as the extremities, vulva, chest wall, and abdominal cavity. This cancer is more prevalent in women and has a poor prognosis with a high rate of recurrence and a significant percentage of metastasis. Case Representation: Herein, we report the case of a 64-year-old female patient who presented with 3-month history of left lower abdominal mass. The patient underwent abdominal malignancy resection and was subsequently diagnosed with myxoid leiomyosarcoma. The patient experienced a recurrence and metastasis with significant ascites after the initial surgery and did not respond to treatment with oral Anrotinib in combination with Tislelizumab immunotherapy. Further genetic testing using next-generation sequencing (NGS) identified missense mutations in the PDGFRA and TP53 genes in the patient's plasma, but no mutations in the KIT gene were detected. Immunohistochemical analysis of the tumor tissue also revealed a negative expression of PD-L1. As a result, we altered her targeted therapy to Avapritinib, which resulted in significant improvement in her symptoms, including abdominal distension and pain, a decrease in ascites, and the KPS score increased from 60 points before treatment to 90 points after treatment SD (stable disease) was achieved for three months after treatment. Conclusion: In this case report, we present the instance of a patient with malignant myxoid leiomyosarcoma with a missense mutation in both the PDGFRA and TP53 genes. We found that targeted therapy with Avapritinib was effective in achieving a positive outcome in this patient. Our findings suggest that genetic detection is possible to better understand the biological behavior, genetic characteristics, and patient's response and tolerance to certain drugs, thus selecting the best treatment plan for the patient. Avapritinib may be a promising new treatment option for leiomyosarcoma patients with similar genetic mutations.

Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs)

BackgroundGastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well...

High-intensity interval training stimulates remyelination via the Wnt/β-catenin pathway in cuprizone-induced demyelination mouse model

ABSTRACT Objectives This study aims to investigate the role of high-intensity interval training (HIIT) in promoting myelin sheath recovery during the remyelination phase in cuprizone (CPZ)-induced demyelination mice and elucidate the mechanisms involving the Wnt/β-catenin pathway. Methods After 5 weeks of a 0.2% CPZ diet to induce demyelination, a 4-week recovery phase with a normal diet was followed by HIIT intervention. Mice body weight was monitored. Morris water maze (MWM) gauged spatial cognition and memory, while the open field test (OFT) assessed anxiety levels. Luxol fast blue (LFB) staining measured demyelination, and immunofluorescence examined myelin basic protein (MBP) and platelet-derived growth factor receptor-alpha (PDGFR-α). Western blotting analyzed protein expression, including MBP, PDGFR-α, glycogen synthase kinase-3β (GSK3β), β-catenin, and p-β-catenin. Real-time PCR detected mRNA expression levels of CGT and CST. Results HIIT promoted remyelination in demyelinating mice, enhancing spatial cognition, memory, and reducing anxiety. LFB staining indicated decreased demyelination in HIIT-treated mice. Immunofluorescence demonstrated increased MBP fluorescence intensity and PDGFR-α+ cell numbers with HIIT. Western blotting revealed HIIT reduced β-catenin levels while increasing p-β-catenin and GSK3β levels. Real-time PCR demonstrated that HIIT promoted the generation of new myelin sheaths. Additionally, the Wnt/β-catenin pathway agonist, SKL2001, decreased MBP expression but increased PDGFR-α expression. Discussion HIIT promotes remyelination by inhibiting the Wnt/β-catenin pathway and is a promising rehabilitation training for demyelinating diseases. It provides a new theoretical basis for clinical rehabilitation and care programs.

Understanding Gastric GIST: From Pathophysiology to Personalized Treatment.

Background: Gastric gastrointestinal stromal tumors (GISTs) represent a subset of gastrointestinal tumors predominantly found in the stomach. Despite their rarity, these tumors carry significant implications for patient health and management. GISTs are potentially malignant tumors with unpredictable progression. They originate from the interstitial cells of Cajal, which are positioned between the intramural neurons and the smooth muscle cells of the digestive tract. These tumors are characterized primarily by mutations in the c-Kit gene, as well as other mutations such as those in the platelet-derived growth factor receptor alpha (PDGFRA) gene. Methods: Our comprehensive search across five databases initially yielded 2976 articles. After eliminating 197 duplicates, we screened the titles and abstracts of 2779 articles, excluding 2692 for not meeting the inclusion criteria. During the full-text screening, 16 more articles were excluded. Ultimately, 71 papers met the inclusion criteria and were included in our analysis. Results: Due to differences in study designs, inclusion criteria for patients, and reported outcomes, a meta-analysis was not conducted. The accurate diagnosis of GIST is established through histopathological examination and immunohistochemistry. Histopathologically, GISTs are classified into three main types: spindle cell, epithelioid, and mixed. The therapeutic management of GIST involves surgery, endoscopic treatment, and chemotherapy. Conclusions: The prognosis for GIST patients depends on various factors, including risk category, disease stage, applied treatments, and recurrence post-treatment. A significant recent advancement comes from artificial intelligence, which can be increasingly involved in both the diagnosis and treatment of this tumor.

Analysis of platelet-derived growth factor receptor alpha expression in adult mouse testis

Analysis of platelet-derived growth factor receptor alpha expression in adult mouse testis

Gastro Intestinal Stromal Tumor: Cases Series Report

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the alimentary tract. Now a day GISTs represents 0.1-3% of all gastrointestinal malignancies, making it a diagnostic challenge. Lesions are frequently located in stomach and proximal small intestine but rarely elsewhere in the abdomen. They are believed to result from mutations of protooncogenes c-Kit or platelet-derived growth factor receptor alpha polypeptide, this increase tyrosine kinase receptor activity, leading to uncontrolled proliferation of stem cells that differentiate into cells of Cajal. They can occur at any age but predominantly in middle-aged people and in elderly. We reported the cases presented to our hospital with progressively distension of the abdomen, finding in diagnostic image suggested GIST without evidence of metastasis disease, total excision was done, Cytologic and immunohistochemistry analysis confirm diagnosis of GISTs.

TRLS-08. ROVER: A PHASE 1/2 TRIAL IN PROGRESS OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING

Abstract BACKGROUND Advanced pediatric solid tumors, including central nervous system (CNS) tumors with PDGFRA and/or KIT mutations/amplifications are aggressive diseases with limited treatment options. KIT alterations occur in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. No KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50&amp;lt;2 nM), and PDGFRA activation-loop (D842V) mutants (half-maximal inhibitory concentration [IC50]=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios, 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved in the USA and Europe to treat adults with indolent systemic mastocytosis, in the USA for adults with advanced systemic mastocytosis (AdvSM), and in Europe for adults with AdvSM after ≥1 prior systemic therapy. Avapritinib is also approved to treat adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA and PDGFRA D842V mutations in Europe. METHODS ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib (once daily, administered in continuous 28-day cycles) in pediatric patients aged 2 to &amp;lt;18 years with relapsed/refractory solid tumors that harbor PDGFRA and/or KIT mutations/amplifications or patients with diffuse midline glioma H3K27-altered (DMG-H3K27a). Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.

HGG-51. INTRANASAL DELIVERY OF PDGFRA-IMMUNOLIPOSOMAL SN-38 FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS

Abstract INTRODUCTION pHGGs are the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the braistem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of liposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the specificity of anti-PDGFRA monoclonal antibody conjugated immunoliposome (PDGFRA-iLS) in pHGG cell lines. METHODS PDGFRA signals were assessed in pHGG cells using western blotting. Cells with high and low expression of PDGFRA were treated with rhodamine (Rho) labeled PDGFRA-iLS and imaged with fluorescent microscope. RESULTS DIPG007, SF7761 and KNS42 expressed high levels of PDGFRA, while SF8628 and DIPG36 cells showed low expression. Fluorescence microscopy revealed high PDGFRA-rhodamine (Rho)-iLS expression in DIPG007 cells (PDGFRA high), relative to SF8628 and DIPG36 cells (PDGFRA low). CONCLUSION PDGFRA-Rho-iLS shows increase cellular uptake in DIPG cells. Work is underway to determine the biodistribution, host toxicity, and anti-tumor activity of IND of PDGFRA-iLS-SN- 38 alone and in combination with radiation therapy in pHGG xenograft models.

DIPG-14. METABOLIC REPROGRAMMING AS A RESISTANCE MECHANISM IN DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline gliomas (DMG) are uniformly fatal pediatric brain cancers, refractory to current standards of care. Based on genomic and transcriptomic profiling data, we previously proposed that platelet-derived growth factor receptor alpha (PDGFRA) is crucial to the tumorigenic potential and maintenance of stem-like DMG cells and that targeting PDGFRA is an important therapeutic avenue in DMG. In comprehensive pre-clinical studies, we identified avapritinib, an FDA-approved PDGFRA inhibitor, to be highly effective in patient-derived xenograft (PDX) DMG models. We further reported the first clinical experience using avapritinib in recurrent DMG and demonstrated preliminary safety, tolerability, and efficacy of the drug in this population. While a subset of patients experienced a strong clinical response from avapritinib, tumor progression was eventually observed in all patients. METHODS Here, we investigated the molecular mechanisms that DMG cells upregulate following avapritinib treatment, with the aim to exploit them therapeutically. To uncover these mechanisms, we performed transcriptomic, metabolic and functional assays along with a combinatorial drug screening. RESULTS Transcriptional analysis of patient-derived DMG cell lines revealed an upregulation of genes associated with fatty acid metabolism and oxidative phosphorylation (OXPHOS) following treatment with avapritinib. Functional assays confirmed elevated OXPHOS in avapritinib-treated cells with significant (i) increase in mitochondrial energy transduction, (ii) increase in palmitate- (a product of fatty acid metabolism) driven oxygen consumption rate and (iii) greater incorporation of palmitate-derived carbons into the tricarboxylic acid cycle. To determine which therapies could target this dependency on OXPHOS and fatty acid metabolism, we performed a metabolic drug screening in patient-derived DMG cell lines and identified two metabolic drugs to have synergistic cytotoxic effects with avapritinib. CONCLUSION We revealed distinct metabolic reprogramming in avapritinib-treated DMG cells and showed that targeting these metabolic vulnerabilities might further increase the clinical benefit of PDGFRA inhibitor avapritinib.

Clinicopathological Characteristics and the First Mutational Analysis of Gastrointestinal Stromal Tumors From Mexico: A Single Institution Experience.

Background Gastrointestinal stromal tumors (GISTs) arise from Cajal's interstitial cell precursors and display a variety of genetic mutations, primarily in the KIT and PDGFRA genes. These mutations are linked to tumor location, prognosis, and response to treatment. This study delves into the mutational patterns of GISTs in a Mexican population and their impact on overall survival (OS) and disease-free survival (DFS). Methodology This retrospective study examined 42 GIST cases diagnosed at the Oncology Hospital of the National Medical Center XXI Century between January 2018 and December 2020. Clinical, histological, and immunohistochemical data were gathered, and mutational analysis of KIT and PDGFRA genes was conducted using second-generation sequencing. Results The study group consisted of 52.4% females and 47.6% males, with an average age of 62.6 years. The most common tumor site was the stomach (59.5%), followed by the small intestine (26.2%). KIT mutations were detected in 71.4% of cases, predominantly involving exon 11. PDGFRA mutations were observed in 7.1% of cases. Recurrence was noted in 9.5% of patients, all with high-risk tumors. No significant link was identified between specific mutations and OS or DFS. Conclusions This investigation sheds light on the genetic landscape of GISTs in the Mexican population. While no significant association was established between particular mutations and survival outcomes, the study emphasizes the importance of molecular profiling in treatment decision-making. Further studies with larger sample sizes and longer follow-up periods are necessary to validate these results and explore their clinical relevance.