Inhibitor Imatinib Research Articles

Genetic alterations in the BCR-ABL1 fusion gene related to imatinib resistance in chronic myeloid leukemia

Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.

Adult Philadelphia-Positive Acute Lymphoblastic Leukemia: A Single-Institution Experience in Limited-Resource Setting.

L. K. RajeevBackground Adult Philadelphia-positive (Ph + ) acute lymphoblastic leukemia (ALL) is a distinct entity with poor prognosis. Treatment with tyrosine kinase inhibitors improved responses but still with poor outcomes. We evaluated treatment outcomes in these patients treated in limited-resource settings in the absence of availability of allogeneic stem cell transplantation (ASCT). Materials and Methods We studied case record files of the adult patients diagnosed with Ph+ ALL. Results A total of 18 patients were evaluated retrospectively. The median age of presentation was 28 years. Male-to-female ratio was 1:1. Patients presented with fever and fatigue. Six patients (33.33%) presented with cervical lymphadenopathy. Clinical splenomegaly was present in 16 (88.88%) patients on palpation, whereas on ultrasonographic evaluation, all 18 patients had splenomegaly. The median size of the spleen was 15 cm. Hepatomegaly was seen in 5 (27%) patients. All 18 patients had anemia at the time of presentation. Leukocytosis was seen in 17 (94.44%) patients, whereas 1 (5.56%) patient presented with low total leukocyte count. The median platelet count at the time of presentation was 30,000/mm. 3 On peripheral smear, median number of blast cells was 55%, and on bone marrow aspiration samples, median blast percentage seen was 70%. Conventional cytogenetics was done in all the patients on bone marrow aspiration samples. Ten patients (55.55%) had t(9;22) - Ph chromosome. One patient (5.56%) on cytogenetics showed double Ph chromosome. The median value of breakpoint cluster region-ABL1 transcript in IS% was 13%. Seventeen (94.44%) received ALL protocol (BFM95) along with tyrosine kinase inhibitor (imatinib). One (5.56%) patient refused aggressive cytotoxic chemotherapy. No patient underwent ASCT. The median duration of follow-up was 7.5 months, ranging from 3 to 16 months. Median overall survival (OS) was 7.5 months and 2-year OS was 33.33%. Conclusion Poor prognosis of this disease, especially in the absence of ASCT, remains a major challenge in the treatment.

Dose optimization strategy of the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib for chronic myeloid leukemia: From clinical trials to real-life settings.

With the advent of tyrosine kinase inhibitors (TKIs), the treatment prospects of chronic myeloid leukemia (CML) have changed markedly. This innovation can lengthen the long-term survival of patients suffering from CML. However, long-term exposure to TKIs is accompanied by various adverse events (AEs). The latter affect the quality of life and compliance of patients with CML, and may lead to serious disease progression (and even death). Recently, increasing numbers of patients with CML have begun to pursue a dose optimization strategy. Dose optimization may be considered at all stages of the entire treatment, which includes dose reduction and discontinuation of TKIs therapy. In general, reduction of the TKI dose is considered to be an important measure to reduce AEs and improve quality of life on the premise of maintaining molecular responses. Furthermore, discontinuation of TKIs therapy has been demonstrated to be feasible and safe for about half of patients with a stable optimal response and a longer duration of TKI treatment. This review focuses mainly on the latest research of dose optimization of imatinib, dasatinib, and nilotinib in CML clinical trials and real-life settings. We consider dose reduction in newly diagnosed patients, or in optimal response, or for improving AEs, either as a prelude to treatment-free remission (TFR) or as maintenance therapy in those patients unable to discontinue TKIs therapy. In addition, we also focus on discontinuation of TKIs therapy and second attempts to achieve TFR.

Imatinib mitigates experimentally-induced ulcerative colitis: Possible contribution of NF-kB/JAK2/STAT3/COX2 signaling pathway

RationaleUlcerative colitis (UC) is a chronic immune-mediated disease characterized by recurrent inflammation, damage, and alteration of the large intestine's mucosal and submucosal surfaces. The purpose of this research was to evaluate the impact of tyrosine kinase inhibitor (imatinib) on experimentally induced UC in rats via acetic acid (AA). MethodsMale rats were randomly assigned to four groups: control, AA, AA + imatinib (10 mg/kg), and AA + imatinib (20 mg/kg). Imatinib (10 and 20 mg/kg/day) was orally supplied by oral syringe for one week before induction of UC. On the eighth day, Rats received enemas containing a 4 % solution of acetic acid to induce colitis. One day after inducing colitis, rats were euthanized and their colons were subjected to morphological, biochemical, histological, and immunohistochemical analysis. ResultsImatinib pretreatment significantly decreased macroscopic and histological damage scores, decreased disease activity index as well as colon mass index. In addition, imatinib successfully lowered the levels of malondialdehyde (MDA) in colonic tissues and enhanced superoxide dismutase activity (SOD) and glutathione content (GSH). Imatinib also reduced colonic levels of inflammatory interleukins (IL-23, IL-17, IL-6), JAK2 and STAT3. Furthermore, imatinib suppressed nuclear transcription factor kappa B (NF-kB/p65) level, and COX2 expression in colonic tissues. SignificanceImatinib may be a viable therapy option for UC as it halts the interaction network of NF-kB/JAK2/STAT3/COX2 signaling pathway.

Co-targeting of ACK1 and KIT triggers additive anti-proliferative and -migration effects in imatinib-resistant gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GIST) harbor mutated receptor tyrosine kinase (RTK) KIT/PDGFRA, which provides an attractive therapeutic target. However, a majority of GISTs ultimately develop resistance to KIT/PDGFRA inhibitor imatinib, multiple therapeutic targets will be identified as a reasonable strategy in imatinib-resistant GISTs. Biological mechanisms of non-RTK activated CDC42 associated kinase 1 (ACK1) are still unclear, which has been found to be activated in GISTs. In the current report, ACK1 overexpression is demonstrated in GIST cell lines and biopsies. RNA-seq analysis and immunoblotting show that ACK1 expression is dependent on imatinib treatment time in GIST-T1 cell line. The colocalization/complex of KIT and ACK1 in GIST cells are observed, and ACK1 activation is in a partially KIT and CDC42 dependent manner. Treatment with a specific ACK1 inhibitor AIM-100 or ACK1 siRNA, mildly suppresses cell viability, but markedly inhibits cell migration in imatinib sensitive and in imatinib resistant GIST cell lines, which is associated with inactivation of PI3K/AKT/mTOR and RAF/MAPK signaling pathways, and inhibition of epithelial-mesenchymal transition, evidencing upregulation of E-cadherin and downregulation of ZEB1, N-cadherin, vimentin, snail, and/or β-catenin after treatment with AIM-100 or ACK1/CDC42 shRNAs. Combination inhibition of ACK1 and KIT results in additive effects of anti-proliferation and pro-apoptosis as well as cell cycle arrest, and inhibition of invasiveness and migration in vitro and in vivo, compared to either intervention alone through dephosphorylation of KIT downstream intermediates (AKT, S6, and MAPK). Our data suggest that co-targeting of ACK1 and KIT might be a novel therapeutic strategy in imatinib-resistant GIST.

Recurrent Retroperitoneal and Subhepatic EGIST – Case Report

Background GISTs (gastrointestinal stromal tumors) are a common mesenchymal tumor of the gastrointestinal tract. It is a diverse pathology that can occur in any portion of the gastrointestinal tract, from distal esophagus to anus. However, the stomach is the most common origin. GISTs evolve from small neoformations, to a large, metastasizing sarcoma. Their pathogenesis is linked with the KIT or PDGFRA mutations. GIST is to be suspected in cases where a round mass is encountered in close relations to the stomach, intestine or lower esophagus. It has to be differentiated with other neuroendocrine tumors, lymphomas and other rare cancers by means of a biopsy. Case presentation The 62 y/o male patient was diagnosed 4 years prior to the current events with GIST for which a surgical procedure of distal pancreatectomy, splenectomy and partial resection of curvatura major of the stomach was performed at another hospital. This was followed by chemotherapy as advised by the treating doctors. The patient presents to our clinic with the complaints of left flank pain for over a week, dysphagia and weight loss. CT shows a giant formation of the left flank, at the splenic lodge, with dimensions of 30 × 32 cm, with close proximity to the left kidney, abdominal aorta, the lienal flexure of colon, the stomach, superior mesenteric artery. Besides this, another 8 × 9 cm subhepatic formation is noted, which has a close vicinity to the portal vein and hepatic hilum. He underwent the surgical procedure for the extirpation of the both masses, also partial resection of curvatura major, vagotomy, Heineke-Mikulicz pyloroplasty, segmental hepatic flexure colon resection and end-to-end anastomosis. The procedure was tolerated well and he was discharged in good health. The following pathology report confirms GIST. Discussion Treatment of GISTs and EGISTs consists on the R0 resection of the mass, without the need for radical removal of healthy tissue since these types of tumors do not normally infiltrate adjacent tissue. If other organs are invaded it is recommended to perform an en-bloc resection, taking care to avoid the rupture of the mass, as to minimize the chances of peritoneal dissemination. A prompt adjuvant therapy including the use of selective tyrosine kinase inhibitors (imatinib) is strongly advised. The patient should be followed with periodic controls for recurrence. Conclusion There is a clear role surgery can play in improving the outcomes in such patients. However, some authors still debate whether surgery improves results in such patients. For this purpose, it is necessary to involve a team of oncologists, imaging specialists and experienced surgeons in the treatment plan of GIST patients to provide the best treatment. Keywords: General Surgery, Retroperitoneal EGIST, Hepatic EGIST, GIST. DOI: 10.7176/JEP/14-9-06 Publication date: March 31 st 2023

Identification of M4205─A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable Metastatic or Recurrent Gastrointestinal Stromal Tumors.

The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example of targeted therapy for treatment of cancer. The approval of the tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under treatment and relapse is observed. Several additional KIT inhibitors have been approved; still, there is a high unmet need for KIT inhibitors with high selectivity and broad coverage of all clinically relevant KIT mutants. An imidazopyridine hit featuring excellent kinase selectivity was identified in a high-throughput screen (HTS) and optimized to the clinical candidate M4205 (IDRX-42). This molecule has a superior profile compared to approved drugs, suggesting a best-in-class potential for recurrent and metastatic GISTs driven by KIT mutations.

Impact of Tyrosine Kinase Inhibitors Applied for First-Line Chronic Myeloid Leukemia Treatment on Platelet Function in Whole Blood of Healthy Volunteers In Vitro.

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, bosutinib, and nilotinib are established for first-line treatment of chronic myeloid leukemia (CML) but may cause side effects such as bleeding and thrombotic complications. We investigated the impact of TKIs on platelet function ex vivo in anticoagulated whole blood (WB) samples from healthy adults by lumiaggregometry and PFA-100 test. Samples (n = 15 per TKI) were incubated for 30 minutes with TKI at therapeutically relevant final concentrations. Aggregation and ATP release were induced by collagen (1 µg/mL), arachidonic acid (0.5 mmol/L), and thrombin (0.5 U/mL). Imatinib, bosutinib, and nilotinib significantly increased collagen-induced aggregation compared with controls. In addition, for bosutinib and nilotinib, a significant increase in aggregation after induction with arachidonic acid was detected. ATP-release and PFA-100 closure times were not influenced significantly by these three TKI. In contrast, dasatinib demonstrated a concentration-dependent inhibition of collagen-induced aggregation and ATP release and a significant prolongation of the PFA-100 closure time with the collagen/epinephrine cartridge. Aggregation and ATP release by other agonists as well as closure time with the collagen/ADP cartridge were not influenced significantly. In conclusion, we clearly show a concentration-dependent inhibition of collagen-induced platelet function in WB by dasatinib confirming prior results obtained in platelet-rich plasma. Bosutinib and nilotinib exerted no impairment of platelet activation. On the contrary, both TKI showed signs of platelet activation. When comparing our results with existing data, imatinib in therapeutic relevant concentrations does not impair platelet function.

Concurrent use of tumor necrosis factor inhibitor and tyrosine kinase inhibitor in ankylosing spondylitis and myeloid neoplasm.

Biologic disease-modifying agents (bDMARDs) are highly effective in controlling the symptoms of autoimmune rheumatic diseases. The decision on whether to continue bDMARDs following a cancer diagnosis can be challenging for patients and physicians. Here, we describe a case of a middle-aged male with ankylosing spondylitis who was controlled on infliximab (IFX) and found to have a myeloid neoplasm with Platelet-Derived Growth Factor Receptor Beta rearrangement. The patient was started on a tyrosine kinase inhibitor imatinib. Given its significant positive effect on patient's quality of life, IFX was continued with a favorable outcome. This case highlights the importance of shared decisionmaking in balancing risks and benefits of immunosuppressants in appropriate cases of hematologic malignancy.

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction

Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.

Treatment de-escalation in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens.

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

Novel design of dual-action Pt(IV) anticancer pro-drugs based on cisplatin and derivatives of the tyrosine kinase inhibitors imatinib and nilotinib.

Tyrosine kinases (TKs) are emerging as important targets in cancer therapy and some of their inhibitors, TKIs (e.g. imatinib and nilotinib), are FDA-approved drugs that are used as selective anti-cancer therapeutics against cell lines that overexpress TKs. Many examples of metal-based complexes functionalised with TKIs are reported in the literature but very few have been functionalised with platinum. Here we report the design, a detailed computational analysis/simulation, the complete chemical characterisation and the preliminary biological evaluation of two novel Pt(IV) anticancer pro-drugs based on cisplatin tethered with a derivative of either imatinib or nilotinib in the axial position. Pt(IV) complexes are a strategic scaffold in combination therapy due to their axial ligands that can be functionalised to form dual action drugs. The activation by reduction releases the Pt(II) core and the axial ligands upon cellular internalisation. The antiproliferative activity and the TK inhibition properties of the novel adducts are analysed with a theoretical approach and confirmed in vitro with preliminary biological assays.

Heavy chain deposition disease (HCDD) of the kidney in a patient of treated chronic myeloid leukemia with imatinib

Chronic myeloid leukemia is a clonal disorder of myeloid origin which transforms into more aggressive phenotypes, either acute myeloid leukemia or acute lymphoblastic leukemia. The long-term outcome of chronic myeloid leukemia has significantly improved with tyrosine kinase inhibitor imatinib. In contrast, heavy chain deposition disease is a disorder of lymphoid origin due to a plasma cell clone classified under monoclonal immunoglobulin deposition disease with truncated monoclonal heavy chain deposition along basement membranes of many organs, predominantly the kidneys causing significant organ dysfunction. The connection between the two disorders seems to be vague and undefined. We report a novel case of treated chronic myeloid leukemia with imatinib in sustained clinical and cytogenetic remission who presented with heavy chain deposition disease of the kidney, causing renal dysfunction and nephrotic range proteinuria that responded to clone-directed therapy. Given these disorders’ two different cell lines, their association could be fortuitous only. However, in the light of a few dozen cases published thus far in which the prototypical plasma cell disorders multiple myeloma and monoclonal gammopathy of undetermined significance have evolved from cases of treated CML, this association seems to be genuine, the possible genesis of which is discussed in this manuscript. Long-term exposure of chronic myeloid leukemia patients to imatinib could predispose some rare, vulnerable patients to a plasma cell disorder, including heavy chain deposition disease.

The Economic Burden of Chronic Myeloid Leukemia in Patients with Later Lines: Findings from a Real-World Analysis in Italy.

Chronic myeloid leukemia (CML) is a hematopoietic myeloproliferative disorder that accounts for 20% of all leukemias of adults. The introduction of tyrosine kinase inhibitors (TKIs) (imatinib, bosutinib, dasatinib, nilotinib, ponatinib) has yielded significant benefits for patients with CML in terms of survival and quality of life. This real-world analysis evaluated the economic burden for managing patients with CML in 2nd or ≥ 3rd TKI lines in Italian settings of clinical practice. A retrospective observational analysis was performed exploiting the administrative databases of a sample of entities covering around 15 million inhabitants. From 2015 to 2018, the study included adult patients with at least one prescription for TKIs, (and for some TKIwithat least one hospitalization discharge diagnosis for CML, or at least one prescription for BCR-ABL examination). The index date was the first TKI prescription. Healthcare resource consumption and costs for patients with CML in 2nd and ≥ 3rd line treatment with TKIs were analyzed for drug prescriptions, hospitalizations, specialist visits, and diagnostic services. In total 635 patients were included, 491 in 2nd line and 144 in 3rd line with TKIs. Dasatinib was the most frequently prescribed drug in 2nd line (28.9%) and imatinib in later lines (26.4%). With progressing lines of treatment, healthcare consumption showed a trend towards increased non-TKI prescriptions per patient (8 for 2nd line and 9.7 for ≥ 3rd line). The management of patients with CML in later lines resulted in increased overall healthcare burden, with hospitalizations accounting for about half of total expenditure, whatever the treatment line and type of TKI. This analysis in Italian real-life clinical practice reported economic expenditure for patients with CML in 2nd or ≥ 3rd lines with TKIs, mostly burdened by hospitalizations. Such clinical complexity suggests that further efforts are needed to improve the therapeutic management of later lines of CML.

GASTROINTESTINAL STROMAL TUMOUR – EXPERIENCE OF A PERIPHERAL TERTIARY CARE INSTITUTE

Introduction- GIST is a generally a rare tumour but it is most common mesenchymal malignancy of gastrointestinal tract . this malignancy originates from the interstitial cells of Cajal, the pacemakers of GI tract. Management of GIST is associated with difculties at diagnosis, proper immunohistochemical categorisation, completeness surgical excision,resistance to available TKIs. Aim of this study was to share the experience of treating GIST case AIMS - Methods- s from a peripherally located tertiary level hospital . In this retrospective observational study all the histology and immunohistochemistry proved cases of GIST attending Department of Radiotherapy of Midnapore Medical College between 2016 to 2017 were accrued and evaluated. 12 Cases were evaluated for their Result - demographic character, clinical presentation , treatment history, response pattern. M:F ratio was 1.4:1.Age range was 37 years to 58 years. Eleven cases were postoperative and 1 case was advanced inoperable. All the cases were positive for KIT stains .All the patients received treatment with Tyrosine Kinase inhibitor Imatinib Mesylate. At the end of 2 yrs of treatment and follow up 10 patients were disease free , two patients developed progression of disease. Introduction of Imatinib Mesylate and other TKIs have Conclusion - revolutionised the management of GISTs. Still the management is associated different obstacles like early diagnosis, proper immunohistochemical and genotypic categorisation, resistance to available TKIs , lack of large scale studies . Further long term studies with larger study population is needed to improve the treatment outcome of patients suffering from this mysterious disease.

Oncological efficiency of wide local excision in dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP) is a slow-growing, low- to intermediate-grade malignant sarcoma. Its optimal treatment is resection with wide margins; the likelihood of local control associated with this procedure exceeds 90%. The probability of regional or distant metastases is <5%. We examined the clinical, epidemiological, and pathological features, the treatment types, and outcomes of patients to investigate the width of safe surgical margins (SM) and how the width of SMs affected recurrence in DFSP. We retrospectively examined the records of 60 patients who were initially operated on with wide local excision for DFSP in the period 2008-2019. Optimal cutoff points for SMs were calculated with the receiver operating characteristic curve analysis and found as 1.925cm histopathologically and 2.26cm macroscopically. During the mean 89.6-month follow-up, local recurrence was seen in 36.7% and distant metastasis in 20% of the patients. Recurrences were significantly related to peripheral resection margins. Analysis by histopathologic cutoff points showed that the local recurrence rate was 84% when SM was ≤1.925cm, but only 2.85% when >1.925cm (p=0.002). Recurrence-free survival was 40.92 months when SM was ≤1.925cm and 225.75 months when s >1.925cm (p<0.001). Analysis by macroscopic cutoff points showed that the local recurrence rate was 95.5% when SM was ≤2.26cm, but only 4% when >2.26cm (p=0.001). Recurrence-free survival was 43 months when SM was ≤2.26cm and 222 months when >2.26cm (p<0.001). In metastatic patients, progression-free survival was 9 months with cytotoxic chemotherapy, whereas 38.4 months with tyrosine kinase inhibitor (imatinib) (p=0.002). This study showed SMs >2.5cm to be sufficiently safe for WLE and optimized the balance among safe margin width, reconstruction need, and surgical morbidity. In metastatic DFSP patients, tyrosine kinase inhibitor imatinib is more effective than cytotoxic chemotherapy for progression-free survival.

Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

Abstract 10554: Major Cardiac Side Effects of BTK and BCR-ABL Kinase Inhibitor Therapy in Cancer Patients: A Global WHO Database Analysis

Introduction: Bruton’s tyrosine kinase (BTK) and BCR-ABL kinase inhibitors have transformed the treatment for hematological cancers, such as mantle cell lymphoma and chronic myelogenous leukemia. However, these therapies present unique cardiac events that remain underexplored. Hypothesis: We hypothesize that the two groups of targeted therapies commonly used to treat hematological cancers will differ in cardiac side-effect profiles. Methods: The World Health Organization database, VigiBase ®, contains over 20 million Individual Case Safety Reports and is maintained by the Uppsala Monitoring Centre. Reports for unique cardiac events associated with the use of BTK and BCR-ABL kinase inhibitors were analyzed. Reporting odds ratios (ROR), 95% confidence intervals (CI) and chi-squared tests were used to compare differences in cardiac side-effect profiles between the two groups of therapies. Results: A total of 24,385 adverse cardiac events from the use of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib) and BCR-ABL kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) have been observed based on records obtained to-date. Compared to BCR-ABL kinase inhibitors, BTK inhibitors have significantly increased reporting for atrial fibrillation (ROR: 6.995; 95% CI: 6.493-7.537; P &lt; 0.001) and ventricular tachycardia (ROR: 1.829; 95% CI: 1.342-2.493; P &lt; 0.001). However, BCR-ABL inhibitors have significantly increased reporting for myocardial infarction (ROR: 2.077; 95% CI: 1.863-2.316; P &lt; 0.001) but similar reporting for congestive cardiac failure (ROR: 0.949; 95% CI: 0.852-1.058; P = 0.343). The median onset of ventricular tachycardia from the use of BTK inhibitors is 176 days (interquartile range: 48-636 days). For BCR-ABL kinase inhibitors, the median onset of ventricular tachycardia is similar at 137 days (interquartile range: 92-396 days), P = 0.741 from nonparametric tests. Conclusion: We conclude that BTK inhibitors are associated with arrhythmic events, while BCR-ABL kinase inhibitors are associated with myocardial infarction. Both groups have similar reporting for congestive cardiac failure. Research is underway to study the mechanisms behind these novel side-effect profiles.

Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma.

Glioblastoma is the deadliest brain cancer. One of the main reasons for poor outcome resides in therapy resistance, which adds additional challenges in finding an effective treatment. Small protein kinase inhibitors are molecules that have become widely studied for cancer treatments, including glioblastoma. However, none of these drugs have demonstrated a therapeutic activity or brought more benefit compared to the current standard procedure in clinical trials. Hence, understanding the reasons of the limited efficacy and drug resistance is valuable to develop more effective strategies toward the future. To gain novel insights into the method of action and drug resistance in glioblastoma, we established in parallel two patient-derived glioblastoma 2D and 3D organotypic multicellular spheroids models, and exposed them to a prolonged treatment of three weeks with temozolomide or either the two small protein kinase inhibitors enzastaurin and imatinib. We coupled the phenotypic evidence of cytotoxicity, proliferation, and migration to a novel kinase activity profiling platform (QuantaKinome™) that measured the activities of the intracellular network of kinases affected by the drug treatments. The results revealed a heterogeneous inter-patient phenotypic and molecular response to the different drugs. In general, small differences in kinase activation were observed, suggesting an intrinsic low influence of the drugs to the fundamental cellular processes like proliferation and migration. The pathway analysis indicated that many of the endogenously detected kinases were associated with the ErbB signaling pathway. We showed the intertumoral variability in drug responses, both in terms of efficacy and resistance, indicating the importance of pursuing a more personalized approach. In addition, we observed the influence derived from the application of 2D or 3D models in in vitro studies of kinases involved in the ErbB signaling pathway. We identified in one 3D sample a new resistance mechanism derived from imatinib treatment that results in a more invasive behavior. The present study applied a new approach to detect unique and specific drug effects associated with pathways in in vitro screening of compounds, to foster future drug development strategies for clinical research in glioblastoma.

Biological screening of a unique drug library targeting MRGPRX2.

Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets and communicate extracellular signals that initiate cellular responses. Recent evidence shows that GPCR MRGPRX2 is of major importance in IgE-independent pseudo-allergic DHRs based on the suspected interactions between many FDA-approved peptidergic compounds and MRGPRX2. Our aim was to uncover novel MRGPRX2-selective and -potent agonists as drug candidates responsible for clinical features of pseudo-allergic DHRs. We conducted a primary high-throughput screening (HTS), coupled with mutagenesis targeting the MRGPRX2 N62S mutation, on a panel of 3,456 library compounds. We discovered pharmacologically active hit compounds as agonists of the MRGPRX2 protein according to high degrees of potency evaluated by the calcium response and validated by the degranulation assay. Using the molecular tool Forge, we also characterized the structure-activity relationship shared by identified hit compounds. The alternative allele of single nucleotide polymorphism rs10833049 (N62S) in MRGPRX2 demonstrated loss-of-function property in response to substance P and antineoplastic agent daunorubicin hydrochloride. We applied a unique assay system targeting the N62S mutation to the HTS and identified 84 MRGPRX2-selective active hit compounds representing diverse classes according to primary drug indications. The top five highly represented groups included fluoroquinolone and non-fluoroquinolone antibiotics; antidepressive/antipsychotic; antihistaminic and antineoplastic agents. We classified hit compounds into 14 clusters representing a variety of chemical and drug classes beyond those reported, such as opioids, neuromuscular blocking agents, and fluoroquinolones. We further demonstrated MRGPRX2-dependent degranulation in the human mast cell line LAD2 cells induced by three novel agonists representing the non-fluoroquinolone antibiotics (bacitracin A), anti-allergic agents (brompheniramine maleate) and tyrosine-kinase inhibitors (imatinib mesylate). Our findings could facilitate the development of interventions for personalized prevention and treatment of DHRs, as well as future pharmacogenetic investigations of MRGPRX2 in relevant disease cohorts.