UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: A study of the Princess Margaret Hospital Phase II consortium

Welch, Stephen; Hirte, Hal W.; Carey, Mark; Hotte, S. J.; Tsao, Ming‐Sound; Brown, Shirley; Pond, Gregory R.; Dancey, Janet; Oza, Amit M.

doi:10.1016/j.ygyno.2007.02.018

Cited by 61 publications

(35 citation statements)

References 19 publications

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“…UCN-01 has been tested in advanced cancer patients in phase I/II clinical trials, both as single agent and in combination with conventional chemotherapeutic drugs (for example, carboplatin, fludarabine or topotecan); however, significant antitumor activities have not yet been reported (Welch et al, 2007). In addition to pulmonary toxicity, nausea/vomiting, lactic acidosis and transaminitis, UCN-01 induced insulin resistance in the clinic.…”

Section: Inhibitors Of the Ser/thr Kinase Activity Of Pdk1mentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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Section: Inhibitors Of the Ser/thr Kinase Activity Of Pdk1mentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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“…In the setting of the cancer types in which CHK1 is an oncogene (35)(36)(37), CHK1 is a potential therapeutic target (41,42). Indeed, CHK1 inhibitors, such as UCN-01 and GÖ6976, have been utilized as sensitizers in preclinical and clinical trials (28,(43)(44)(45). The p53 pathway is crucial, but not required, for the targeting of CHK1 in cancer (46).…”

Section: Figurementioning

confidence: 99%

CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma

Hong¹,

Hu²,

Yuan

et al. 2012

J. Clin. Invest.

106

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Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.

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“…One potential clinical challenge for the use of UCN-01 as a tumor treatment is the sensitization of normal tissues due to the broad spectrum of its targets. Increased myelosuppression was seen in phase I clinical trials of UCN01 with topotecan at lower doses than when topotecan was used alone (29,30). With increasingly selective inhibitors and biomarkers it is likely that better therapeutic indexes can be achieved in clinical settings.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Recent Advances in Cancer Therapy Targeting Proteins Involved in DNA Double-Strand Break Repair

Bolderson

Richard

Zhou

et al. 2009

Clinical Cancer Research

169

131

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Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1-or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio-and chemotherapy. The challenge is how to identify those patients most receptive to these treatments. (Clin Cancer Res 2009;15(20):6314-20)

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UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: A study of the Princess Margaret Hospital Phase II consortium

Cited by 61 publications

References 19 publications

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma

Recent Advances in Cancer Therapy Targeting Proteins Involved in DNA Double-Strand Break Repair

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