A Phase I Study of AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) Given on Days 1, 4 8, 12 & 15 of an Every 21-day Cycle in Adult Patients With Refractory or Metastatic Solid Malignancies

Camptothecins are a potent class of anticancer drugs that inhibit DNA Topoisomerase I. While seen strictly as cytotoxic compounds, camptothecins are actually also targeted agents, inhibiting DNA-Topoisomerase I (Topo I) cleavable complex. First and second generation cogeners are hampered by a labile α-hydroxy-δ-lactone pharmacophore, which hydrolyzes to yield the inactive carboxylate form of the drug. AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog engineered to be stable in blood and highly potent. Its enhanced stability results from two factors: (1) AR-67 is highly lipophilic, partitioning into lipid bilayers, thus protecting it from hydrolysis in the aqueous milieu of the bloodstream, and (2) the 10-hydroxy functionality of the drug effectively ablates the high affinity interactions of the carboxylate drug form with albumin, which has been previously shown to diminish the levels of the active lactone species in the circulation. In a recently completed phase I trial, AR-67 showed over 85% lactone stability at all time points studied, and was well-tolerated with grade 4 thrombocytopenia, neutropenic fever and grade 3 fatigue as dose limiting toxicities. The MTD was established at 7.5 mg/m2/day in a daily times five of a 21 day cycle. Preclinical data indicates that AR-67 may concentrate in tumors for a prolonged period of time, compared to plasma clearance of the drug, a phenomenon which has the potential to improve efficacy and decrease toxicity of this compound. What is not known is the optimal dose and schedule of AR-67 needed to produce high tumor penetration, and modest systemic exposure. This pilot proposal seeks to study AR-67 in a novel dosing schedule and to evaluate the feasibility of performing tumor biopsies to determine the tumor half-life of AR-67 in humans. By using multiple tumor biopsies, as a means to document penetration of tumor tissue by AR-67, and compare that to plasma clearance of the drug, the investigators will establish direct pharmacokinetic evidence that AR-67 "hits the target". The investigators propose that a rigorous evaluation of drug penetration into the tumor should be considered, in addition to the MTD, when determining dose of new experimental compounds. Dose-tumor concentration relationships should be established early in the course of clinical development to provide data for rational selection of the phase-II dose. This pilot study will provide important preliminary data to establish the feasibility of this approach for future study. If successful, tumor half life will be used to develop an optimal biologic dose in a phase I trial using this schedule of AR-67. Optimal biologic dosing could become a new standard for dose escalation studies with this compound and other cytotoxic drugs that have specific biologic targets in the future.

Start Date01 Sep 2010

Sponsor / Collaborator

University of Kentucky

[+1]

NCT01124539

/ Unknown statusPhase 2

A Phase 2 Study of AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin) in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma

The primary objective of this study is to determine the 6-month Progression free survival (PFS) when intravenous (IV) AR-67 is administered in adults with confirmed recurrence of GBM who have not recently (> 90 days) recurred after treatment bevacizumab (including patients who've received temazolamide, but no bevacizumab). The primary objective in the rapid bevacizumab failure group (< 90 days) is to determine the 2-month PFS.

Start Date01 Dec 2009

Sponsor / Collaborator

Arno Therapeutics, Inc.

NCT00956787

/ Unknown statusPhase 2

Phase 2 Study of AR-67 (DB-67) in Myelodysplastic Syndrome(MDS)

The purpose of this study is to determine if AR-67 is effective in the treatment for patients with MDS.

Start Date01 Jun 2009

Sponsor / Collaborator

Arno Therapeutics, Inc.

100 Clinical Results associated with AR-67

100 Translational Medicine associated with AR-67

100 Patents (Medical) associated with AR-67

Literatures (Medical) associated with AR-67

03 Aug 2025·Autophagy

Chaperone-mediated autophagy degrades SERPINA1 ^E342K /α1-antitrypsin Z variant and alleviates cell stress

Article

Author: Lu, Haorui ; Dai, Yan ; Wu, Rihan ; Rao, Lang ; Lin, Jiayu ; Yang, Hao ; Song, Yajian ; Ju, Jiansong ; Cao, Qichen ; Wei, Xinyue

Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSPA8/HSC70 for substrate recognition. In SERPINA1/a1-antitrypsin deficiency (AATD), a disease characterized by the hepatic buildup of the SERPINA1^E342K/ATZ, CMA's role had been unclear. This work demonstrates the critical role that CMA plays in preventing SERPINA1^E342K/ATZ accumulation; suppressing CMA worsens SERPINA1^E342K/ATZ accumulation while activating it through chemical stimulation or LAMP2A overexpression promotes SERPINA1^E342K/ATZ breakdown. Specifically, SERPINA1^E342K/ATZ's ₁₂₁QELLR₁₂₅ motif is critical for HSPA8/HSC70 recognition and LAMP2A's charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of SERPINA1^E342K/ATZ. This selective activation of CMA operates independently of other autophagy pathways and alleviates SERPINA1^E342K/ATZ aggregate-induced cellular stress. In vivo administration of AR7 promotes hepatic SERPINA1^E342K/ATZ elimination and mitigates hepatic SERPINA1^E342K/ATZ aggregation pathology. These findings highlight CMA's critical function in cellular protein quality control of SERPINA1^E342K/ATZ and place it as a novel target for AATD treatment.Abbreviation: AR7: atypical retinoid 7; ATG16L1: autophagy related 16 like 1; AATD: SERPINA1/alpha-1 antitrypsin deficiency; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; MG132: carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; PAS-D: periodic acid-Schiff plus diastase; SERPINA1/A1AT: serpin family A member 1; SERPINA1^E342K/ATZ: Z variant of SERPINA1; TMRE: tetramethyl rhodamine ethyl ester perchlorate.

01 Apr 2024·Life sciences

Comprehensive pan-cancer analysis identifies the RNA-binding protein LRPPRC as a novel prognostic and immune biomarker

Article

Author: Kang, Ning ; Liu, Xinyue ; Wu, Zheng ; Jin, Di ; Xie, Fang ; Yan, Jinsong ; Ma, Chao ; Lam, Eric W-F ; Jin, Bilian

AIMS:

RNA-binding proteins (RBPs) play pivotal roles in carcinogenesis and immunotherapy. Leucine-rich pentapeptide repeat-containing protein (LRPPRC) is crucial for RNA polyadenylation, transport, and stability. Although recent studies have suggested LRPPRC's potential role in tumor progression, its significance in tumor prognosis, diagnosis, and immunology remains unclear.

MAIN METHODS:

We comprehensively analyzed LRPPRC expression in tumors using various databases, including Human Transcriptome Cell Atlas (HTCA), University of California Santa Cruz (UCSC), Human Protein Atlas (HPA), Sangerbox, TISIDB, GeneMANIA, GSCALite, and CellMiner. We examined the correlation between LRPPRC expression level and prognosis, immune infiltration, immunotherapy, methylation, biological function, and drug sensitivity. Single-cell analysis was performed using Tumor Immune Single Cell Hub (TISCH) and CancerSEA software. Patients with acute myeloid leukemia (AML) were categorized based on LRPPRC levels for functional and immune infiltration analyses. The role of LRPPRC in cancer was validated using in vitro experiments.

KEY FINDINGS:

Our findings revealed that LRPPRC was highly expressed in almost all cancer types, indicating its significant prognostic and diagnostic potential. Notably, LRPPRC was associated with diverse immune features, such as immune cell infiltration, immune checkpoint genes, tumor mutational burden, and microsatellite instability, suggesting its value in guiding immunotherapy strategies. Within AML, the high-expression group had lower levels of immune cells, including CD8+ T cells. In vitro experiments confirmed the inhibitory effects of LRPPRC knockdown on AML cell proliferation.

SIGNIFICANCE:

This study highlights LRPPRC as a reliable pan-cancer prognostic and immune biomarker, particularly in AML. It lays the groundwork for future research on LRPPRC-targeted cancer therapies.

01 Feb 2020·Autophagy

Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA)

Article

Author: Ramsden, David Boyer ; Lam, Colin Siu-Chi ; Ho, Shu-Leong ; Liu, Huifang ; Pang, Shirley Yin-Yu ; Ho, Philip Wing-Lok ; Xian, Jiawen ; Leung, Chi-Ting ; Li, Lingfei ; Kung, Michelle Hiu-Wai

Parkinson disease (PD) is an age-related neurodegenerative disorder associated with misfolded SNCA/α-synuclein accumulation in brain. Impaired catabolism of SNCA potentiates formation of its toxic oligomers. LRRK2 (leucine-rich repeat kinase-2) mutations predispose to familial and sporadic PD. Mutant LRRK2 perturbs chaperone-mediated-autophagy (CMA) to degrade SNCA. We showed greater age-dependent accumulation of oligomeric SNCA in striatum and cortex of aged LRRK2^R1441G knockin (KI) mice, compared to age-matched wildtype (WT) by 53% and 31%, respectively. Lysosomal clustering and accumulation of CMA-specific LAMP2A and HSPA8/HSC70 proteins were observed in aged mutant striatum along with increased GAPDH (CMA substrate) by immunohistochemistry of dorsal striatum and flow cytometry of ventral midbrain cells. Using our new reporter protein clearance assay, mutant mouse embryonic fibroblasts (MEFs) expressing either SNCA or CMA recognition 'KFERQ'-like motif conjugated with photoactivated-PAmCherry showed slower cellular clearance compared to WT by 28% and 34%, respectively. However, such difference was not observed after the 'KFERQ'-motif was mutated. LRRK2 mutant MEFs exhibited lower lysosomal degradation than WT indicating lysosomal dysfunction. LAMP2A-knockdown reduced total lysosomal activity and clearance of 'KFERQ'-substrate in WT but not in mutant MEFs, indicating impaired CMA in the latter. A CMA-specific activator, AR7, induced neuronal LAMP2A transcription and lysosomal activity in MEFs. AR7 also attenuated the progressive accumulation of both intracellular and extracellular SNCA oligomers in prolonged cultures of mutant cortical neurons (DIV21), indicating that oligomer accumulation can be suppressed by CMA activation. Activation of autophagic pathways to reduce aged-related accumulation of pathogenic SNCA oligomers is a viable disease-modifying therapeutic strategy for PD.Abbreviations: 3-MA: 3-methyladenine; AR7: 7-chloro-3-(4-methylphenyl)-2H-1,4-benzoxazine; CMA: chaperone-mediated autophagy; CQ: chloroquine; CSF: cerebrospinal fluid; DDM: n-dodecyl β-D-maltoside; DIV: days in vitro; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GWAS: genome-wide association studies; HSPA8/HSC70: heat shock protein 8; KFERQ: CMA recognition pentapeptide; KI: knockin; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LDH: lactate dehydrogenase; LRRK2: leucine-rich repeat kinase 2; MEF: mouse embryonic fibroblast; NDUFS4: NADH:ubiquinone oxidoreductase core subunit S4; NE: novel epitope; PD: Parkinson disease; RARA/RARα: retinoic acid receptor, alpha; SNCA: synuclein, alpha; TUBB3/TUJ1: tubulin, beta 3 class III; WT: wild-type.

News (Medical) associated with AR-67

03 May 2021

·www.biospace.com

Vivacitas Oncology and IAG Partner to Integrate Novel Imaging Markers in the Development of AR-67 in Recurrent Glioblastoma Patients

WALNUT CREEK, CA and LONDON, UK / ACCESSWIRE / May 3, 2021 / Vivacitas Oncology, Inc. ("Vivacitas" or the "Company"), a clinical stage biopharmaceutical company focused on tough to treat cancers, and Image Analysis Group ("IAG"), a leading global medical imaging company, are collaborating to apply Artificial Intelligence (AI) technology and advanced imaging strategies to further the development of AR-67, a third generation Camptothecin, in patients with recurrent glioblastoma multiforme (reGBM). Advanced imaging techniques could play a critical role in response assessment in developing new and innovative cancer therapies. Multiparametric magnetic resonance imaging (mpMRI) provides quantitative non-invasive imaging markers of early therapy-related changes. IAG is deploying its proprietary, cloud-based imaging approach to provide scientific evidence of early therapy response. Tina Runk, Vivacitas co-founder and Executive Vice President of Clinical Operations stated, "Working with IAG, we performed a retrospective analysis of imaging data from our Phase 2 clinical study of AR-67 activity in recurrent GBM, in which their technology was applied to assess pseudoprogression from true progression of disease. This assessment capability demonstrates the benefit of potentially including this technology in future pivotal clinical trials and treatment regimens to ensure patient retention based on more detailed and objective criteria." Dr. Diana Dupont-Roettger, the Chief Scientific Alliance Officer at IAG stated, "We are excited to bring the latest and most impactful imaging strategies to Vivacitas to ensure a scientific excellence and efficient drug development process." ABOUT VIVACITAS ONCOLOGY: Vivacitas Oncology is a private clinical stage biopharmaceutical company focused on combating those cancers that have proven to be frustratingly resistant to current treatment modalities. It originated with the vision of Dr. Joseph Rubinfeld (co-founder of Amgen) with the intent to improve upon well known chemotherapies with demonstrated effect, but which also possess challenges with potency, toxicity, stability, and other issues limiting their use. Through an enduring spirit, Vivacitas continues to apply clarity, tenacity, and vision in our fight against intractable cancers and our pursuit of new treatment options for patients and their families worldwide. For further information please visit or Elise@vivaoncology.com. ABOUT IAG: Image Analysis Group (IAG) is a unique clinical development partner to life sciences companies. IAG broadly leverages its proprietary image analysis methodologies, power of our cloud platform DYNAMIKA, years of experience in AI and Machine Learning as well as bespoke co-development business models to ensure higher probability for promising therapeutics to reach the patients. Our independent Bio-Partnering division fuses risk-sharing business models and agile culture to accelerate novel drug development. For further information please visit or reach out to imaging.experts@ia-grp.com. SOURCE: Vivacitas Oncology, Inc. View source version on accesswire.com:

100 Deals associated with AR-67

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Phase 2	United States	Arno Therapeutics, Inc.	01 Dec 2009
Glioblastoma Multiforme	Phase 2	Canada	Arno Therapeutics, Inc.	01 Dec 2009
Gliosarcoma	Phase 2	United States	Arno Therapeutics, Inc.	01 Dec 2009
Gliosarcoma	Phase 2	Canada	Arno Therapeutics, Inc.	01 Dec 2009
Metastatic Solid Tumor	Phase 1	United States	Arno Therapeutics, Inc.	01 Oct 2006
Neoplasms	Preclinical	United States	University of Pittsburgh	19 Sep 2000

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SNO2021	Phase 2	Recurrent Glioblastoma	8	AR-67	iazogqjdlv(ryuqjcdafo) = dmanqxykoc kfesskvgsm (eqgjagzeys ) View more	Positive	12 Nov 2021
				Placebo	iazogqjdlv(ryuqjcdafo) = vrkqlrjqij kfesskvgsm (eqgjagzeys ) View more

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