Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. ...Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Aerobic glycolysis, featured with elevated glucose consumption and lactate production, confers selective ...advantages on GBM by utilizing nutrients to support rapid cell proliferation and tumor growth. Pyruvate kinase 2 (PKM2), the last rate-limiting enzyme of glycolysis, is known to regulate aerobic glycolysis, and considered as a novel cancer therapeutic target. Herein, we aim to describe the cellular functions and mechanisms of a small molecular compound dimethylaminomicheliolide (DMAMCL), which has been used in clinical trials for recurrent GBM in Australia. Our results demonstrate that DMAMCL is effective on the inhibition of GBM cell proliferation and colony formation. MCL, the active metabolic form of DMAMCL, selectively binding to monomeric PKM2 and promoting its tetramerization, was also found to improve the pyruvate kinase activity of PKM2 in GBM cells. In addition, non-targeting metabolomics analysis reveals multiple metabolites involved in glycolysis, including lactate and glucose-6-phosphate, are decreased with DMAMCL treatment. The inhibitory effects of DMAMCL are observed to decrease in GBM cells upon PKM2 depletion, further confirming the importance of PKM2 in DMAMCL sensitivity. In conclusion, the activation of PKM2 by DMAMCL results in the rewiring aerobic glycolysis, which consequently suppresses the proliferation of GBM cells. Hence, DMAMCL represents a potential PKM2-targeted therapeutic agent against GBM.
Selective cyclin-dependent kinase (cdk) 2 inhibition is readily compensated. However, reduced cdk2 activity may have antiproliferative effects in concert with other family members. Here, inducible ...RNA interference was used to codeplete cdk2 and cdk1 from NCI-H1299 non-small cell lung cancer and U2OS osteosarcoma cells, and effects were compared with those mediated by depletion of either cdk alone. Depletion of cdk2 slowed G1 progression of NCI-H1299 cells and depletion of cdk1 slowed G2-M progression in both cell lines, with associated endoreduplication in U2OS cells. However, compared with the incomplete cell cycle blocks produced by individual depletion, combined depletion had substantial consequences, with G2-M arrest predominating in NCI-H1299 cells and apoptosis the primary outcome in U2OS cells. In U2OS cells, combined depletion affected RNA polymerase II expression and phosphorylation, causing decreased expression of the antiapoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis (XIAP), effects usually mediated by inhibition of the transcriptional cdk9. These events do not occur after individual depletion of cdk2 and cdk1, suggesting that reduction of cdk2, cdk1, and RNA polymerase II activities all contribute to apoptosis in U2OS cells. The limited cell death induced by combined depletion in NCI-H1299 cells was significantly increased by codepletion of cdk9 or XIAP or by simultaneous treatment with the cdk9 inhibitor flavopiridol. These results show the potency of concomitant compromise of cell cycle and transcriptional cdk activities and may guide the selection of clinical drug candidates.
A subset of lung cancers expresses mutant forms of epidermal growth factor receptor (EGFR) that are constitutively activated. Cancers bearing activated EGFR can be effectively targeted with EGFR ...inhibitors such as erlotinib. However, the death-signaling pathways engaged after EGFR inhibition are poorly understood. Here, we show that death after inhibition of EGFR uses the mitochondrial, or intrinsic, pathway of cell death controlled by the BCL-2 family of proteins. BCL-2 inhibits cell death induced by erlotinib, but BCL-2-protected cells are thus rendered BCL-2-dependent and sensitive to the BCL-2 antagonist ABT-737. BH3 profiling reveals that mitochondrial BCL-2 is primed by death signals after EGFR inhibition in these cells. As this result implies, key death-signaling proteins of the BCL-2 family, including BIM, were found to be up-regulated after erlotinib treatment and intercepted by overexpressed BCL-2. BIM is induced by lung cancer cell lines that are sensitive to erlotinib but not by those resistant. Reduction of BIM by siRNA induces resistance to erlotinib. We show that EGFR activity is inhibited by erlotinib in H1650, a lung cancer cell line that bears a sensitizing EGFR mutation, but that H1650 is not killed. We identify the block in apoptosis in this cell line, and show that a novel form of erlotinib resistance is present, a block in BIM up-regulation downstream of EGFR inhibition. This finding has clear implications for overcoming resistance to erlotinib. Resistance to EGFR inhibition can be modulated by alterations in the intrinsic apoptotic pathway controlled by the BCL-2 family of proteins.
Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting STAT3 and NF-κB pathways, has shown activity in preclinical models of DMG. We evaluated safety, toxicity and activity of ACT001 ...in this recently completed, first-in-child study of DMG and other relapsed/refractory brain and solid tumors. METHODS Eligible patients ≥ 1 and ≤ 21 years old were enrolled with dose escalation following a rolling 6 design and tumor lesions evaluated every 8 weeks per RANO/ RECIST criteria. RESULTS A total of 29 patients were enrolled across 5 cohorts, including 19 with DMG (13 with Diffuse Intrinsic Pontine Glioma (DIPG)). Median age was 11 years for the whole cohort and 7 years (3-17) for DMG patients. Safety was evaluated in escalating doses in 188, 533, 700, 875 and 1100 mg/m2,BID cohorts. No DLT nor grade 3 and above TRAE was identified. One SUSAR was noted for a grade 1 pain in extremity event. Peak ACT001 concentration for each dose cohort were estimated based on limited PK sampling time (cycle 1 day 1 at pre-dose, 2 and 4 hours post dose; cycle 1 day 15 and cycle 2 day 1 both at pre-dose). ACT001 peak concentration plateaued at the highest dose levels, fluctuating in the range of 6360, 5430 and 5980 mg/m2 for 700, 875 and 1100 mg/m2 cohorts respectively. The half-life was approximately 3 hours. 8/14 DMG patients treated at ≥ 700 mg/m2 exhibited objective response or stable disease (SD), including one patient with SD for 14 months, another patient with confirmed Partial Response who remained on study for 11-months before disease progression and five other patients with different degrees of tumor burden reduction. CONCLUSION ACT001 was well tolerated and showed preliminary evidence of anti-tumor activity in DMG/DIPG patients dosed at the highest dose levels. A Phase 2 trial is planned using 875 mg/m2 as the RP2D.
Abstract
BACKGROUND
Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) ...and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence.
RESULTS
7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study.
CONCLUSIONS
ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.
AND-34 is a murine protein that binds by a cdc25-like GDP exchange factor domain to the focal adhesion docking protein p130Cas. Overexpression of either of the human homologues of AND-34 and p130Cas, ...BCAR3 and BCAR1, respectively, has been reported to induce resistance to antiestrogens in breast cancer cell lines. Here we show that overexpression of AND-34 leads to activation of the Rho family GTPases Cdc42 and Rac. Consistent with these findings, BCAR3 overexpression induced alterations in F-actin distribution and augmented both autophosphorylation and kinase activity of the Cdc42/Rac-responsive serine/threonine kinase PAK1. p130Cas-associated BCAR3 protein was detected in the estrogen-independent breast cancer cell line 578-T, but not in estrogen-dependent MCF7 or ZR-75-1 cells. Stable ZR-75-1 transfectants overexpressing BCAR3, but not vector-only transfectants, grew in the presence of the pure antiestrogen ICI 182,780. Stable transfection with RacV12, a constitutively active form of Rac1, also induced antiestrogen resistance in ZR-75-1 cells. Transient transfection of BCAR3 in estrogen-dependent MCF7 cells induced activation of luciferase constructs containing the proximal 1745 or 163 bp but not 66 bp of the cyclin D1 promoter. Such cyclin D1 promoter activation was inhibited by dominant negative forms of Rac1 and PAK1. Overexpression of the PAK1 autoinhibitory domain (residues 83-149) but not an inactive PAK1 autoinhibitory domain point mutant (L107F) also blocked BCAR3-mediated cyclin D1 activation. These studies suggest that AND-34/BCAR3 induces antiestrogen resistance in breast cancer cell lines by a Rac1- and PAK1-dependent pathway.
e14006
Background: Parthenolide-derived compounds, including ACT001, achieved radiation-enhancing and normal cell protection effects in pre-clinical studies through Nrf2, STAT3 and other pathways. ...Safety and efficacy data from 45 cancer patients with brain metastasis in a phase 1b/2a study were presented. Methods: Eligible patients with SCLC, NSCLC and other cancers complicated with more than three metastatic brain lesions (no up limit for SCLC) were randomized to placebo (Cohort C), ACT001 200mg (Cohort A) and 400mg,bid (Cohort B). Patients were treated with ACT001 or placebo in combination with WBRT (30 Gy/10f) in first two weeks followed by continuous treatment with ACT001 or placebo till disease progression. Treatment emergent adverse events (TEAEs, the primary endpoint) and survival events were monitored. TE-SAEs and OS events that happened within 3 months (for lung cancers) or 6 months (other cancers) after end of WBRT were also assessed. MRI scans were performed and evaluated in baseline, 30 and 90 days after end of WBRT during study per iRANO and RANO-BM criteria. Results: Study enrolled 22 patients with SCLC, 14 NSCLC, 7 breast cancer and 2 with other cancers. NSCLC patients were negative for EGFR, ALK and ROS1 mutations whereas breast cancer patients are negative for HER2. Patient characteristics were balanced in age, KPS and GPA scores. All subjects finished the required WBRT. As of Dec 31
st
, 2021, a total of 7 (9), 13 (13) and 10 (11) patients in Cohort C, A and B respectively had post-treatment MRI scans for objective response evaluation per iRANO (or RANO-BM) criteria. Of note, the patient numbers reflected those whose tumors met radiologically evaluable lesion requirements per iRANO (> 10mm) or RANO-BM criteria (≥10mm). 3 out of 7 patients (42.9%) in Cohort C, 11 out of 13 (84.6%) in Cohort A and 9 out of 10 (90.0%) patients in Cohort B presented with partial response for intracranial lesions per iRANO criteria whereas 3 out 9 (33.3%), 11 out of 13 (84.6%) and 10 out of 11 (90.9%) patients achieved a partial response per RANO-BM criteria. The increased objective response noted in two ACT001 cohorts was also associated with decreased percentage change of median SPD (sum of the products of perpendicular diameters )as compared with data in Cohort C: -66.1% (Cohort A, baseline 969.8 mm
2
), -72.3% (Cohort B, baseline 445.3 mm
2
) and -44.7% (Cohort C, baseline 506.9 mm
2
). There were 41, 30 and 20 WBRT-related grade 2 and 3 adverse events in Cohorts C, A and B. respectively. In total, there were 6, 4 and 2 TE-SAEs and death events reported in non-accumulative manner in Cohorts C, A and B respectively. As of this report, one year PFS for intracranial lesions has not been determined due to limited PD events. Conclusions: ACT001 seemed to ameliorate WBRT-induced adverse events and reduce intracranial burden of tumor metastasis. A pivotal study is warranted to further evaluate these effects. Clinical trial information: ChiCTR2000037739.
Abstract only
2037
Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in ...preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC
0-last
were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.
Abstract only
2044
Background: Management of advanced gliomas including glioblastoma multiforme (GBM) remains as an unmet medical need. Here we report our clinical experience with ACT001, or ...dimethylamino micheliolide, a synthesized derivative from parthenolide (a natural product of sesquiterpene lactone class), in Han Chinese patients with advanced glioma. Methods: Adult patients were enrolled in a 3+3 dose escalation phase 1 study with the following pre-defined ACT001 cohorts: 100mg, 200mg, 400mg, 600mg and 900mg, twice a day (BID). Pharmacokinetics and adverse events were evaluated during the study. Imaging studies were performed using RANO criteria to assess the therapeutic afficacy. Results: 16 patients with advanced glioma were enrolled in this single agent dose escalation study including 8 primary GBM, 4 astrocytoma (grade 2-3) and 4 other advanced glioma. The median age was 49 years (range: 31-70). Safety evaluation was performed in five cohorts and 13 of the 16 subjecst were evaluable for drug tolerability analysis. ACT001 was tolerated very well and no DLT or MTD was identified. Other than grade 1 adverse reactions (AE) in most cases and grade 2 AEs in other clinical findings, no drug-related grade 3 AE was noted. Pharmacokinetic analysis indicates that there was approximately linear correlate between the drug exposure (C
max
, AUC
0-t
and AUC
0-inf
) and study drug dosages evaluated. T
1/2
is 4 hours with mean Cmax increased from approximate 300ng/ml to 5000ng/ml in a dose dependent manner with no significant dose accumulation during repeated dosing challenge. Post baseline MRI scans were performed in 11 out of 16 subjects. Among these 11 subjects, 1 GBM patient had a partial response (PR) at end of cycle 2 but had disease progressed at end of cycle 4; two non-GBM patients had a stable disease (SD) lasting for 5 or 6 cycles respectively before being taken off study due to disease pregression (PD) and other 8 patients had a PD. Of note, 9 out of these 11 subjects had stable or even improved clinical performance by the time they were taken off study due to PD. Five other subjects withdrew their consents or were taken off study due to clinical disease progression. Of note, subject S12 with diffusive astrocytoma was taken off study due to PD while still with a stable clinilcal performance and stereotactic biopsies targeting the progressed lesion didn’t reveal viable tumor tissues other than presence of macrophage/microglia. This subject was still alive 666 days after being taken off study. The mode of ACT001 actions is proposed to be at least partially related to its effects on tumor immune microenvironment. Conclusions: ACT001 was safe and tolerated well in patients. Clinical response was observed including a pathologic response in a subset of patients dosed at lower dose cohorts. iRANO criteria will be used in future studies based on its impacts on tumor immune microenvitonment. Clinical trial information: ChiCTR-OIC-17013604.
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