A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), a Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors

Lockhart, A. Craig; Howard, Martin; Hande, Kenneth R.; Roth, Bruce J.; Berlin, Jordan; Vreeland, Franzanne; Campbell, Angela; Fontana, E.; Fiorentini, F.; Fowst, Camilla; Paty, Victoria A.; Lankford, Odessa; Rothenberg, Mace L.

doi:10.1158/1078-0432.ccr-0658-03

Cited by 19 publications

(13 citation statements)

References 18 publications

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“…5). Interestingly, synthetic derivatives of distamycin A, an anticancer agent that targets the ability of MEF2 proteins to interact with DNA (53), are currently in phase I clinical trials (54). Future studies are aimed at determining which MEF2 family members are expressed in a majority of breast cancer cells, how they may contribute to breast cancer biology, and if they are key targets of Brk-regulated signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells

et al. 2007

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Total tyrosine kinase activity is often elevated in both cytosolic and membrane fractions of malignant breast tissue and correlates with a decrease in disease-free survival. Breast tumor kinase (Brk; protein tyrosine kinase 6) is a soluble tyrosine kinase that was cloned from a metastatic breast tumor and found to be overexpressed in a majority of breast tumors. Herein, we show that Brk is overexpressed in 86% of invasive ductal breast tumors and coexpressed with ErbB family members in breast cancer cell lines. Additionally, the ErbB ligand, heregulin, activates Brk kinase activity. Knockdown of Brk by stable expression of short hairpin RNA (shRNA) in T47D breast cancer cells decreases proliferation and blocks epidermal growth factor (EGF)-and heregulininduced activation of Rac GTPase, extracellular signalregulated kinase (ERK) 5, and p38 mitogen-activated protein kinase (MAPK) but not Akt, ERK1/2, or c-Jun NH 2 -terminal kinase. Furthermore, EGF-and heregulin-induced cyclin D1 expression is dependent on p38 signaling and inhibited by Brk shRNA knockdown. The myocyte enhancer factor 2 transcription factor target of p38 MAPK and ERK5 signaling is also sensitive to altered Brk expression. Finally, heregulin-induced migration of T47D cells requires p38 MAPK activity and is blocked by Brk knockdown. These results place Brk in a novel signaling pathway downstream of ErbB receptors and upstream of Rac, p38 MAPK, and ERK5 and establish the ErbBBrk-Rac-p38 MAPK pathway as a critical mediator of breast cancer cell migration. [Cancer Res 2007;67(9):4199-209]

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Section: Discussionmentioning

confidence: 99%

Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells

et al. 2007

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“…23 To avoid the use of subtherapeutic doses of romidepsin and bortezomib in patients with advanced MM, we used a novel accelerated dose escalation schedule in which cohorts of one new patient per dose level were enrolled during the initial accelerated stage of the trial. [24][25][26][27] Accelerated titration designs are more aggressive than standard approaches and therefore may be associated with a greater risk of unpredictable toxicity to individual patients. However, they have the capacity to significantly reduce the number of "undertreated" patients.…”

Section: Introductionmentioning

confidence: 99%

A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma

Harrison

Quach

Link

et al. 2011

Blood

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We report results from a study exploring the combination of romidepsin, bortezomib, and dexamethasone for the treatment of patients with multiple myeloma (MM) previously treated with > 1 prior therapy. The primary objective was to determine the maximum tolerated dose (MTD) of the combination using a novel accelerated dose-escalation schedule in patients with relapsed or refractory MM. The secondary objective was to determine overall response (OR), time to progression (TTP), and overall survival (OS).

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“…Alkylating agents based on the minor groove binder distamycin A, including tallimustine and brostallicin, have shown improvements over nonconjugated DNA-alkylating agents in terms of affinity and specificity at the nucleotide level (12 -15). However, these compounds possess only limited specificity (16), and myelotoxicity is still the dose-limiting factor in establishing an effective chemotherapy (12,13).…”

Section: Introductionmentioning

confidence: 99%

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

Chou

Farkas

Tsai

et al. 2008

Molecular Cancer Therapeutics

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We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(4):769 -78]

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A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), a Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors

Abstract: ABSTRACT

Cited by 19 publications

References 18 publications

Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells

Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells

A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

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