Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development

Park, John W.; Kerbel, Robert S.; Kelloff, Gary J.; Barrett, J. Carl; Chabner, Bruce A.; Parkinson, David; Peck, Jonathan; Ruddon, Raymond W.; Sigman, Caroline C.; Slamon, Dennis J.

doi:10.1158/1078-0432.ccr-03-0785

Cited by 149 publications

(84 citation statements)

References 92 publications

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“…A critical issue in cancer drug development is the discovery of biomarkers of response. 56,57 Our finding of decrease of phospho-Akt and phospho-ERK in response to HMBA suggests that these prognostic markers may become valuable indicators of response to HMBA. Furthermore, the status of PTEN tumor suppressor in breast cancer is correlated with tumor stage and response to therapy.…”

Section: Discussionmentioning

confidence: 90%

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

Dey¹,

Wong²,

Kua³

et al. 2008

Cell Cycle

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Hexamethylene Bisacetamide (HMBA) is a hybrid polar compound originally developed as a differentiation inducing agent. We show in this study that HMBA can inhibit activation of several NFκB target genes in both lung and breast cancer cell lines. Furthermore, consistent with its ability to inhibit NFκB function, HMBA can also sensitize cells to apoptosis. We show that HMBA mediates inhibition of the Akt and ERK/MAPK cascade, both of which are critical for cell survival and proliferation and are well known regulators of NFκB activation. We also show that PTEN negative breast cancer cells which have hyper activation of the PI3K/Akt pathway show increased sensitivity to growth inhibitory effects of combination of HMBA and TNFα. Furthermore, HMBA can decrease the kinase activity of the IKK complex leading to defective phosphorylation of IκBα and Ser536 of p65. This study gives mechanistic insight into the mechanism of action of HMBA, provides the rationale for the potential use of HMBA in combination with various existing kinase inhibitors in combination therapy and also suggests useful biomarkers for monitoring tumor response to HMBA.

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Section: Discussionmentioning

confidence: 90%

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

Dey¹,

Wong²,

Kua³

et al. 2008

Cell Cycle

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“…More recently, inhibition of CHK1 function by knockdown of protein expression by small interfering RNA and several more selective CHK1 inhibitors have confirmed these early observations (19)(20)(21). As a part of the development of molecularly targeted kinase inhibitors, particularly those that might not have antitumor activity in their own right, it is important to identify appropriate biomarker readouts (22,23). Consequently, the development of CHK1 inhibitors and the characterization of suitable biomarkers have become an important drug development objective (24)(25)(26)(27)(28).…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 84%

The Preclinical Pharmacology and Therapeutic Activity of the Novel CHK1 Inhibitor SAR-020106

Walton

Eve

Hayes

et al. 2010

Molecular Cancer Therapeutics

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Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromised G 1 -S checkpoint control. This has led to the hypothesis that S and G 2 -M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53-deficient background, as normal cells would be rescued at the G 1 -S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage-linked S and G 2 -M checkpoint control. SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC 50 of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G 2 arrest with an IC 50 of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0-to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased γH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.

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“…Given that traditional endpoints such as RR may not be useful with agents such as pazopanib, biomarkers for response to VEGF-directed therapy are needed to identify patients most likely to benefit from such treatment. Currently, there are no such validated predictive clinical biomarkers [38,39].…”

Section: Discussionmentioning

confidence: 99%

A Phase II Study of Pazopanib in Patients with Recurrent or Metastatic Invasive Breast Carcinoma: A Trial of the Princess Margaret Hospital Phase II Consortium

et al. 2010

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Purpose. Angiogenesis is an important hallmark of breast cancer growth and progression. Pazopanib, an oral small molecule inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and KIT, has activity across a range of solid tumors. We evaluated the activity of singleagent pazopanib in recurrent or metastatic breast cancer (MBC).Patients and Methods. Patients with recurrent breast cancer or MBC, treated with up to two prior lines of chemotherapy, were eligible to receive pazopanib, 800 mg daily until progression. The primary endpoint was the objective response rate as measured by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included time to progression, the stable disease rate, and toxicity. Using a two-stage design, confirmed response in three of 18 patients was required to proceed to stage 2.Results. Twenty evaluable patients were treated, with a median age of 56 years; 70% were estrogen receptor positive, all were human epidermal growth factor receptor 2 negative. The majority had one or two prior lines of chemotherapy. One patient (5%) had a partial response, 11 (55%) had stable disease

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Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development

Cited by 149 publications

References 92 publications

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

The Preclinical Pharmacology and Therapeutic Activity of the Novel CHK1 Inhibitor SAR-020106

A Phase II Study of Pazopanib in Patients with Recurrent or Metastatic Invasive Breast Carcinoma: A Trial of the Princess Margaret Hospital Phase II Consortium

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