Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising ...clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3′UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.
•A wide range of sensitivity to abemaciclib is observed among Rb+ tumor cells•CDKN2A mutant cancers show only intermediate sensitivity to CDK4/6 inhibition•D-cyclin activating features are associated with highly sensitive cells•About 5% of endometrial cancers bear a stabilizing mutation in the CCND1 3′UTR
Gong et al. identify a subset of cancers highly sensitive to CDK4/6 inhibition, which are characterized by various genomic aberrations known to elevate D-cyclin levels but not by CDKN2A mutations. They also identify a recurrent CCND1 3′UTR mutation associated with increased CCND1 expression in endometrial cancer.
Aims
There is a need for a brief, validated measure of quality of life (QOL) for children to monitor their adjustment to burn injuries. We aimed to apply a Rasch analysis to an existing measure of ...QOL from the dermatology literature to a clinical sample of pediatric burn patients.
Methods
The Children’s Dermatology Life Quality Index (CDLQI) was administered to pediatric burn patients (
N
= 253) during a standard clinic visit. Rasch analysis was used to examine psychometric properties of this measure with a burn sample.
Results
The CDLQI showed an adequate fit to the Rasch model. Test difficulty is .61 logits greater than person ability. Results of item reliability and separation analyses were sufficiently strong and indicated a unidimensional latent trait. Person reliability (.74) and separation analyses (1.64) were moderate. Finally, the CDLQI was able to moderately separate the group of respondents into low and high levels of QOL impairments related to burn injuries.
Conclusion
The Rasch model demonstrated that the CDLQI is a reliable and valid scale that adequately measures QOL impairments in children following burn injuries.
Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, ...inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m
2
, 12–24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m
2
. Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.
Summary
The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering ...and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (K
i
) of 2 nM, a pharmacodynamic residence time (K
off
) of 0.00132 min
−1
and t
1/2
of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).
Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has ...not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75–90 mg/m
2
/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m
2
, days 1, 15) and temozolomide (150 mg/m
2
/day days 1–5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3–29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.
Abstract
Background
Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of ...CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG.
Methods
Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed.
Results
Nineteen patients enrolled (median age: 8 years range: 2-18). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression.
Conclusion
The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.
Abstract
BACKGROUND: Dual inhibition of CDK4/6 and mTOR in DIPG and pediatric HGG has strong biologic rationale, given prevalent genetic alterations resulting in upregulated cell cycle and PI3K/mTOR ...pathways in these diseases, as well as non-overlapping agent toxicities. This study sought to evaluate safety/tolerability and determine the recommended phase 2 dose (RP2D) of ribociclib and everolimus among children with newly diagnosed DIPG and HGG post-radiotherapy. METHODS: Patients were enrolled according to a Rolling-6 design and received oral ribociclib and everolimus once daily for 21 and 28 days, respectively, starting 2-4 weeks post-completion of radiotherapy. All HGG and biopsied DIPG patients were screened for RB protein presence by immunohistochemistry. Pharmacokinetics and survival data were analyzed.
RESULTS: Nineteen patients enrolled (median age: 8 years range: 2-18). Three patients enrolled at each of dose levels 1 and 2 without dose-limiting toxicities (DLTs). Thirteen patients enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy prior to cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9±0.9-fold higher than single-agent administration. Median overall survival (OS) for 15 patients with DIPG was 13.9 months, with 12-, 24-, and 36-month OS of 53.3%, 38.9%, and 38.9%. Median event-free survival for four patients with HGG was 10.5 months. Among patients with tumor molecular profiling, two longer survivors (OS: 20, >37 months) had evidence of cell cycle upregulation with CDKN2A/B deletion and CDK4 overexpression identified. CONCLUSIONS: The combination of ribociclib and everolimus was well-tolerated post-radiotherapy in children with newly diagnosed DIPG and HGG, with a RP2D of ribociclib 170 mg/m2 days 1-21 and everolimus 1.5 mg/m2 days 1-28. Results will inform a molecularly-guided phase II study currently underway to evaluate efficacy.
Abstract
Many cancers are under replicative stress (RS) arising from the combined influence of oncogenic drivers (i.e. Cyclin E, E2F, Myc), genomic instability and/or deficiencies in DNA Damage ...Repair (DDR). Tumors survive RS by upregulating checkpoints such as those driven by the ATR/CHK1 pathway. Dependence of tumors under high RS on the Chk1 pathway is currently being explored in the clinic with the Chk1 kinase inhibitor prexasertib. Preclinical and clinical studies have demonstrated evidence of efficacy in various cancers supporting the notion that this drug has the potential to improve the standard of care for patients with these malignancies. Two pivotal steps to ultimately fulfill the promise of a novel therapeutic in the clinic are, 1) to enable a patient selection strategy via predictive biomarkers of drug response or de novo resistance; 2) to gain insight into mechanisms underlying the development of acquired resistance, a common phenomenon of cancer therapeutics that contributes to non-durable response. Two experimental objectives to address these challenges for prexasertib were set, 1) to profile a large pan-cancer tumor cell line panel for prexasertib response and explore the association between drug response and baseline molecular profile via transcriptomic profiling, (2) to establish an in vitro tumor line with acquired resistance to prexasertib and characterize it via transcriptomic and targeted proteomic profiling to probe the mechanism of acquired resistance to prexasertib. Key observations from this study: A) pathways corresponding to E2F targets, G2M checkpoint and the Spindle Assembly Checkpoint (SAC), with a distinct enrichment for replication fork genes emerged across three different studies, (a) across a pan-cancer tumor line panel associated with prexasertib sensitivity, (b) associated with resistance in a tumor cell line with acquired resistance to prexasertib and (c) as top hits in an unbiased functional shRNA screen aimed at identifying genes that upon knockdown sensitize the resistant tumor cell line to prexasertib. B)knockdown of specific replication fork components in the drug-resistant tumor line was associated with marked sensitization to prexasertib and concomitant evidence of RS and DNA damage.To explain these paradoxical observations, we postulate that tumors may upregulate the expression of E2F target/G2M/SAC genes to resist oncogene-induced RS and that they may rely on similar genes to survive prexasertib-induced RS. Based on this data, transcriptomic profiling may prove of utility in the identification of patient tailoring biomarkers for prexasertib and as tool to unravel mechanisms of acquired resistance.
Citation Format: Wayne D. Blosser, Jack A. Dempsey, Ann M. McNulty, Wenjuan Wu, Philip J. Ebert, Jason C. Ting, Yue W. Webster, Trent R. Stewart, Xueqian Gong, Farhana F. Merzoug, Sean Buchanan, Ricardo Martinez. Enhanced gene expression of replication fork and other E2F targets genes is associated with sensitivity and, paradoxically, also with acquired drug resistance, to the Chk1 inhibitor prexasertib abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2535.
Abstract
KRAS is altered in ~16% of all cancers and is an oncogenic driver in non-small cell lung, pancreatic, colorectal, and other cancers. Next generation KRAS inhibitors designed to target ...multiple oncogenic KRAS mutations, while simultaneously sparing wild-type (WT) HRAS and NRAS inhibition, are expected to offer expanded activity and favorable safety. We have discovered a series of highly potent and selective pan-KRAS inhibitors with activity against KRAS G12C, G12D, and G12V mutants, that also display high selectivity over WT HRAS and NRAS, thus providing an expanded therapeutic index. Here, we describe the preclinical profile of these pan-KRAS inhibitors. Compound potency and selectivity were measured using surface plasmon resonance (SPR) assays and cell-based assays measuring inhibition of p-ERK and 3D cell growth of KRAS-mutant tumor cell lines. These pan-KRAS inhibitors have IC50 values ranging from 3-14 nM for KRAS G12C, G12D, G12V, and WT KRAS in phospho-ERK cell-based assays and selectivity of >200-fold over NRAS WT and >100-fold over HRAS WT. These pan-KRAS inhibitors show a clean safety profile in a 133 off-target panel screen. These pan-KRAS inhibitors demonstrate favorable in vitro ADME properties and oral bioavailability in preclinical species. Tumor growth inhibition and PK/PD studies were performed in mice. In vivo, the pan-KRAS inhibitors administered orally demonstrated dose-dependent target inhibition in KRAS-mutant xenograft models. These data demonstrate that our pan-KRAS inhibitors potently and selectively inhibit KRAS G12D, G12C, and G12V mutations and WT KRAS, while sparing HRAS, NRAS, and other off-targets. We hypothesize that this potency and selectivity profile, along with high oral bioavailability, will provide efficacy and tolerability for patients with KRAS-mutant-driven cancers. An IND submission is planned in 2024.
Citation Format: Lourdes Prieto Vallejo, Chandrasekar Iyer, Noelle Goggin, Binghui Li, Peiyi Yang, Huimin Bian, Jessica Podoll, Stefan Grotegut, Manuj Tandon, Bryan D Anderson, Andrew Capen, Min Xiao, Tao Wang, Trent R Stewart, Sean Aronow, Desta Bume, Isabel Rojo Garcia, Chong Si, Andrew Cooke, Robert Bondi, Lakshmi Kelamangalath, Ross Wallace, Gabrielle Kolakowski, Lauire LeBrun, James R Henry, Tim Kercher. Preclinical characterization of orally bioavailable, highly potent pan-KRAS inhibitors with selectivity over HRAS and NRAS abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B116.
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