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.

NCT00389480

/ CompletedPhase 1

A Phase I Study of DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) in Adult Patients With Refractory or Metastatic Solid Malignancies

Hypothesis:
AR-67 (formerly DB-67) represents a rationally engineered drug that possesses improved stability, toxicity, and efficacy compared to current Food and Drug Administration (FDA)-approved camptothecins, based on the extensive research of prior studies. Therefore, the investigators hypothesize that AR-67 (formerly DB-67) will be well-tolerated and efficacious in phase I clinical trials. This initial phase I trial will establish the maximum tolerated dose in humans, establish the toxicity profile, and define the appropriate dose of AR-67 (formerly DB-67) for future phase II and III clinical trials.

Start Date01 Oct 2006

Sponsor / Collaborator

Arno Therapeutics, Inc.

[+2]

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

01 Apr 2024·Life sciences

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

Article

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

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.

17 Jul 2020·Natural product researchQ3 · CHEMISTRY

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents

Q3 · CHEMISTRY

Article

Author: Morris-Natschke, Susan L. ; Liu, Hua ; Yang, Guan-Zhou ; Zhang, Zhi-Jun ; Song, Zi-Long ; Li, Jun-Cai ; Yang, Chen-Jie ; Lee, Kuo-Hsiung ; Goto, Masuo ; Liu, Ying-Qian

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13 g (IC₅₀ = 0.514 μM) and 13o (IC₅₀ = 0.275 μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC₅₀ = 0.511 μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.

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

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12384

R&D Status

10 top R&D records.

to view more data

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

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


CTNI-45 (SNO2021)	Phase 2	Recurrent Glioblastoma	8	AR-67	lxtyjnzfzk(wmsugwhmql) = vurwepdgum mjtuuxuyxc (fmnvniqfli ) View more	Positive	12 Nov 2021
				Placebo	lxtyjnzfzk(wmsugwhmql) = fswqyedhyf mjtuuxuyxc (fmnvniqfli ) View more

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