Initial Clinical Trial of Oral TAC-101, a Novel Retinoic Acid Receptor-Alpha Selective Retinoid, in Patients With Advanced Cancer

Rizvi, Naiyer A.; Marshall, John L.; Ness, Elizabeth; Hawkins, Michael; Kessler, Craig M.; Jacobs, Helena M.; Brenckman, Wayne D.; Lee, Jin S.; Petros, William P.; Hong, Waun Ki; Kurie, Jonathan M.

doi:10.1200/jco.2002.02.090

Cited by 33 publications

(16 citation statements)

References 14 publications

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“…RAR-specific retinoids are being developed and evaluated in the hope of improved specificity and a reduced side effect profile over conventional pan-RAR agonists. 12,58 The identification of pathways specific for the distinct RARs, such as Mad1 and p27 Kip1 for RAR␣-mediated cell cycle arrest pathways, may allow a more rational application of these compounds. Our study also reveals that RAR␥-induced differentiation of granulocyte progenitors occurs independent of Mad1 and p27 Kip1 status, highlighting potential differences in target genes among the RARs that may be able to be therapeutically exploited.…”

Section: Discussionmentioning

confidence: 99%

Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

Walkley

Purton

Snelling

et al. 2004

Blood

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Retinoids are potent inducers of cell cycle arrest and differentiation of numerous cell types, notably granulocytes. However the mechanisms by which retinoids mediate cell cycle arrest during differentiation remain unclear. We have used myeloid differentiation to characterize the molecular pathways that couple cell cycle withdrawal to terminal differentiation. Using primary cells from mice deficient for either the cyclin-dependent kinase inhibitor (CDKi) p27 Kip1 , the Myc antagonist Mad1, or both Mad1 and p27 Kip1 , we observed that signals mediated through reti- IntroductionThe roles of retinoids during hematopoiesis, particularly granulopoiesis, have been recognized for many years. Most strikingly, retinoids are powerful inducers of differentiation. 1 This effect is central to the use of all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL), a leukemia characterized by a chromosomal translocation always involving retinoic acid receptor ␣ (RAR␣). 2,3 Pharmacologic doses of ATRA are able to relieve the repression caused by the fusion proteins via directly binding and activating them and promoting cell cycle arrest and differentiation of the leukemic blasts. 3 However, the mechanisms by which ATRA mediates cell cycle arrest as well as differentiation remain unclear. An understanding of the molecular basis of this effect will provide important insights into how cell cycle withdrawal is coupled to terminal differentiation and how retinoids interact with the cell cycle.The effects of retinoid ligands are mediated through direct binding to the ligand-binding domain of RARs or retinoid X receptors (RXRs), members of the nuclear hormone receptor superfamily. 4 RARs heterodimerize with RXRs, and this heterodimer binds DNA at retinoic acid response elements (RAREs) in the regulatory sequences of target genes. When unliganded, RAR/RXR heterodimers bind RARE and form repressive complexes through binding SMRT-and NCo-R-containing corepressor complexes. 5 Ligand binding triggers the release of the corepressor complexes and coactivator complexes are recruited to the RAR/ RXR dimer and activate gene transcription. [6][7][8] Three isotypes of RARs and RXRs have each been identified: ␣, ␤, and ␥, with each RAR isotype expressed as a number of isoforms. 4 RAR␣ and RAR␥ are believed to be most important in the regulation of granulopoiesis. 4,9 This is most strikingly demonstrated in progenitor assays of bone marrow cells derived from RAR␣1 Ϫ/Ϫ RAR␥ Ϫ/Ϫ mice. These cells displayed a block in granulopoiesis at the myelocyte stage of development, revealing an absolute requirement for RAR-mediated signaling in the terminal differentiation of granulocytes. 9 Our understanding of the mechanisms through which RAR␣ mediates cell cycle arrest and differentiation of myeloid cells is a question of particular relevance. First, RAR␣, but not RAR␤ or RAR␥, is involved in the pathogenesis of myeloid leukemia. 10 RAR␣ is involved in leukemia both as a fusion partner, most commonly involving promyelocytic leukemia...

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Section: Discussionmentioning

confidence: 99%

Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

Walkley

Purton

Snelling

et al. 2004

Blood

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“…Through its binding to RAR , TAC-101 interferes with the binding of AP-1 to DNA, and inhibits production of urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9). In several studies, TAC-101 has shown inhibition of tumor growth and hepatic metastases in several cancers including colorectal, gastric, pancreatic, and lung cancer and inhibits angiogenesis via down regulation of vascular endothelial growth factor (VEGF) mRNA and protein in a colon cancer model (Hashimoto et al 1996;Murakami et al 1998a, b;Oikawa 1998;Fujimoto et al 1999;Miyaguchi et al 2001;Oikawa et al 2001;Rizvi et al 2002;Lee et al 2003;Miyagawa et al 2003;Sano et al 2003;Satake et al 2003;Yoshimura et al 2003;Minagawa et al 2004;Shudo et al 2004;Suzuki et al 2004;Sako et al 2005). In a gastric cancer animal model, TAC-101 was shown to decrease cellinduced angiogenesis (decreased microvessel density and new blood vessel formation).…”

Section: Discussionmentioning

confidence: 96%

“…The initial doseescalation study of TAC-101 in patients with advanced cancer showed a similar toxicity proWle. (Rizvi et al 2002) Retinoids are capable of inhibiting growth and inducing diVerentiation in tumor models, including HCC (Yasuda et al 2002;Matsushima-Nishiwaki et al 2003). In clinical studies, retinoids have demonstrated potential beneWt in both the prevention and treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma

Higginbotham

Lozano

Brown

et al. 2008

J Cancer Res Clin Oncol

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“…In general, the toxic effects of TAC-101 were consistent with those of previous studies. (7,8) Higginbotham et al reported the results of pharmacokinetic studies of TAC-101 in patients with advanced hepatocellular carcinoma treated in the United States. (8) The mean pharmacokinetic parameters (t max , 4.3 h; C max , 242 ng/mL; AUC 0-24 , 3067.6 ng h/mL; AUC inf , 4241.1 ng h/mL) obtained for a dose of 20 mg were generally consistent with our data in Japanese patients.…”

Section: Discussionmentioning

confidence: 99%

“…VTE developed in nine of 29 patients as a characteristic adverse reaction of TAC-101; the dose ranged from 12 to 34 mg/m 2 . (7) In a phase I/II study, TAC-101 was administered orally in 21-day cycles (14 days on/7 days off) to patients with advanced HCC. In the phase I portion of the study, the initial dose was 40 mg/day.…”

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confidence: 99%

Phase I study of TAC‐101, an oral synthetic retinoid, in Japanese patients with advanced hepatocellular carcinoma

Okusaka¹,

Ueno²,

Ikeda

et al. 2012

Cancer Science

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Preclinical models have shown that TAC‐101 (4‐[3,5‐bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has antitumor activity in hepatocellular carcinoma (HCC). We conducted a phase I study in Japanese patients with advanced HCC to examine the pharmacokinetics, recommended dose, safety, and efficacy of TAC‐101. The administered dose of TAC‐101 was 10 mg/day in four patients (level 1), 20 mg/day in six (level 2), and 30 mg/day in three (level 3). There was no dose‐limiting toxicity at level 1. Only one patient each had dose‐limiting toxicity at level 2 (grade 2 fatigue, recovery requiring eight or more consecutive days of rest) and at level 3 (grade 3 splenic vein thrombosis). Level 3 (30 mg/day) was considered the maximum tolerated dose and 20 mg/day the recommended dose by a panel of medical experts, placing maximum emphasis on safety. The most frequent adverse events were fatigue, headache, and dermal symptoms such as rash. Pharmacokinetic parameters in Japanese patients with HCC were similar to those in patients in the United States, most of whom were Caucasian. Although no patient had a complete or partial response, the disease control rate was 38.5%. In conclusion, the recommended dose of TAC‐101 for patients with HCC is 20 mg/day. TAC‐101 had an acceptable toxicity profile, warranting further evaluation in clinical trials. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02334.x, 2012)

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Initial Clinical Trial of Oral TAC-101, a Novel Retinoic Acid Receptor-Alpha Selective Retinoid, in Patients With Advanced Cancer

Cited by 33 publications

References 14 publications

Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma

Phase I study of TAC‐101, an oral synthetic retinoid, in Japanese patients with advanced hepatocellular carcinoma

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