We welcome the insightful contribution of Pirl et al 1 to the growing literature on the potential neuropsychiatric effects of molecular-targeted cancer therapies.As Pirl et al appropriately point out, the term tyrosine kinase inhibitors (TKIs) was used in our initial paper to refer to a variety of small molecule drugs with activity against a number of different receptor and nonreceptor tyrosine kinases, including imatinib (inhibitory against ABL, BCR-ABL, KIT, and platelet-derived growth factor receptors [PDGFRs]), sunitinib (inhibitory against KIT, PDGFRs, and vascular endothelial growth factor receptors), and dasatinib (inhibitory against ABL, BCR-ABL, SRC, KIT and PDGFRs).Our observations may indeed be quite different from what one might expect to see with the exquisitely specific drugs, such as gefitinib or erlotinib, which inhibit the epidermal growth factor receptor (EGFR).Interestingly, small-molecule TKIs targeting EGFR tend to be far more specific for this receptor tyrosine kinase than for other kinase targets, probably reflecting a unique structural biology for the adenosine triphosphate-binding pocket in the EGFR.Moreover, our observations were derived solely from our team's extensive experience managing GI stromal tumor, one of the three major diseases managed with drugs in this class (the others being chronic myelogenous leukemia and renal cell carcinoma).Of note, links between depression and specific drug exposure may be missed in large database analyses, for multiple reasons.Most importantly, the linkage may be idiosyncratic and/or uncommon.Our observations suggest the incidence of imatinib-associated depression in the GI stromal tumor population to be no more than 2%; many toxicity analyses are reported only if the toxicity is severe or if it occurs in at least 5% to 10% of exposed patients.Second, if the possibility of causality from drug is not considered, depression in a patient suffering from advanced cancer may not be scored as a drug-associated toxicity.Only after recognition of the syndrome in patient 1 were we able to consider and subsequently clinically confirm the diagnosis in other patients in the series.Until further studies are conducted, because of the high morbidity and mortality associated with underdiagnosed and undertreated depression, we believe that the possibility of drug induc-tion of depression or other mood changes should be considered in the differential diagnosis of psychological distress in patients treated with these agents.
10044 Background: Sunitinib malate (SU) is the primary therapy for metastatic gastrointestinal stromal tumor (GIST) resistant to imatinib mesylate (IM). Its inhibition of multiple receptor tyrosine kinases (TK) raised concerns that SU may impair healing after cytoreductive procedures more than IM. We reviewed our experience to compare the spectrum of postoperative complications after SU v. IM therapy. Methods: All patients (pts) with IM-resistant metastatic GISTs enrolled in phase II/III SU protocols at our institution were reviewed. The control group underwent cytoreduction on IM. Perioperative SU dosing and complications after surgery and after resumption of SU were recorded. Complications related to healing included wound/fascial dehiscence, anastomotic leak, and fistula. Complications not attributed to wound healing included hemorrhage, abscess, seroma, and ileus. Results: We treated 188 pts with IM-resistant metastatic GISTs with SU. Twenty-six pts on SU and 46 pts on IM underwent 28 and 53 operations for disease resection, respectively ( Table ). SU was stopped a median of 5 days (range 0–26) prior to surgery and resumed a median of 33 days (range 12–183) after surgery and 20 days (range 7- 178) after hospital discharge, generally during the first postoperative clinic visit. There were 17 complications after 14 (50%) of 28 procedures on SU and 23 complications after 20 (38%) of 53 procedures on IM (p=NS). Dehiscence, leaks, or fistulas, were identified after 2 (7%) procedures on SU and 4 (8%) procedures on IM (p=NS). These 2 pts with complications on SU stopped the drug 9 and 22 days prior to surgery. No wound healing complications were noted among the 18 pts who stopped SU less than 9 days before surgery. Conclusions: Wound healing complications were not more common after extensive resections on SU than on IM, despite SU's inhibition of a wider spectrum of TKs. Our current practice is to continue SU until 1–2 days prior to surgery and to resume SU at the first postoperative visit. [Table: see text] No significant financial relationships to disclose.
Abstract Metabolic lesions with profound effects on epigenetic regulation are widely implicated in cancer, yet the mechanistic links between this epigenetic dysregulation and tumorigenesis remain unclear. Succinate dehydrogenase (SDH) deficiency, responsible for a subset of gastrointestinal stromal tumors (GISTs), causes accumulation of the metabolite succinate and DNA hypermethylation. We identified convergent mechanisms involving altered chromosomal conformation and pseudo-hypoxia that mediate the tumorigenic effects of SDH deficiency in GIST. To investigate epigenetic alterations in this disease, we created epigenetic maps of 14 clinical GIST specimens; including KIT and PDGFRA mutant, and SDH-deficient tumors. We characterized the landscapes of enhancers, genetic regulatory elements which can drive gene expression, through histone H3 lysine 27 acetylation chromatin immunoprecipitation sequencing (ChIP-seq). We characterized both the DNA methylation and CTCF occupancy of insulators, elements which help control chromatin conformation and restrict enhancer-gene interactions, through hybrid selection bisulfite sequencing and CTCF ChIP-seq, respectively. Analyzing these data, we uncovered thousands of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. One of the strongest disrupted insulators protected the receptor tyrosine kinase and known driver of GIST, c-KIT, from a nearby superenhancer. Chromatin conformation studies confirmed an SDH-deficient-specific interaction of this superenhancer with the KIT gene. CRISPR-mediated excision of the insulator in an SDH-intact GIST model resulted in enhancer interaction and KIT upregulation. Immunohistochemical studies confirm strong expression of c-KIT in SDH-deficient GIST clinical samples. SDH deficiency has also been reported to cause pseudohypoxia in tumors. We confirmed that the enhancer landscape of SDH-deficient tumors had a signature of pseudohypoxia. Additionally, following pseudohypoxia induction in a SDH-intact GIST model, the c-KIT ligand Stem Cell Factor (SCF/KITLG) was upregulated 12-fold. While activating KIT mutations drive the majority (~75%) of GIST tumors and are mutually exclusive with SDH deficiency, we show that a primary consequence of SDH loss is in fact induction of KIT signaling. Our findings demonstrate how metabolic lesions can provide alternate epigenetic mechanisms to activate classic tumorigenic pathways in the absence of canonical genetic mutations. Citation Format: William A. Flavahan, Yotam Drier, Sarah E. Johnstone, Daniel R. Tarjan, Esmat Hegazi, Ewa T. Sicinska, Matthew L. Hemming, Chandrajit P. Raut, Jason L. Hornick, George D. Demetri, Bradley E. Bernstein. Insulator dysfunction and epigenetic oncogene activation in SDH-deficient gastrointestinal stromal tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2996.
Quizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy.This was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib.Thirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease.The MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors.Clinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.
Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) holds valuable insights into dysfunctional differentiation given its well- and dedifferentiated histologic subtypes (WDLPS, DDLPS). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human LPS samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 loss was associated with worse overall survival in LPS patients. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS led to a block in differentiation that could not be fully overcome with the addition of exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease.
