Many anticancer drugs target DNA resulting in activation of cell cycle checkpoints, arrest of proliferation, and repair, the consequence of which is recovery and survival of the tumor cells. Current efforts to enhance tumor cell killing include combining anticancer agents with inhibitors of DNA checkpoints. Chk1 has been identified as a critical kinase for cell cycle arrest and many inhibitors are currently in preclinical and clinical development;the current studies focus on the Chk1 inhibitor MK-8776. Recent results have identified a second critical function of Chk1 whereby it prevents the collapse of stalled replication forks. Accordingly, Chk1 inhibitors can dramatically sensitize cells to antimetabolites such as hydroxyurea and gemcitabine. Recently we discovered that stalled replication forks evolve to become more Chk1 dependent with time. This is critical to the development of Chk1 inhibitors as it impacts the timing of drug delivery in clinical trials. An additional observation s that some cell lines are hypersensitive to MK-8776 alone while others are completely resistant. The hypersensitive cell lines also require much less MK-8776 to sensitize them to hydroxyurea or gemcitabine. Accordingly, we hypothesize that a subset of tumors exist that will be highly responsive to the combination of MK-8776 plus either hydroxyurea or gemcitabine. This proposal will assess the variation in response to these drugs across a panel of cell lines and dissect the underlying mechanisms.
The specific aims will 1) define the mechanism(s) for differential sensitivity of human tumor cell lines to MK-8776 as a single agent;2) define the critical step(s) that occur at stalled replication forks that render them more Chk1 dependent with time;and 3) confirm the differential response of human cell lines when grown as xenograft tumors. In addition to establishing the underlying mechanisms, this research will define the optimum schedule of drug administration and biomarkers that can identify patients whose tumors are most likely to respond. This information will be critical for the design of clinical trils and selection of appropriate patients to treat.

Public Health Relevance

Personalized medicine will require the identification of numerous subsets of patients that are uniquely sensitive to particular drugs or combinations. This proposal builds on our observation that subsets carcinoma cell lines are hypersensitive to the inhibition of Chk1. Furthermore, inhibition of Chk1 dramatically sensitizes tumor cells to several established anticancer drugs including the antimetabolites hydroxyurea and gemcitabine. Accordingly, we hypothesize that the combination of a Chk1 inhibitor and an appropriate antimetabolite will dramatically improve therapeutic outcome for patients with sensitive tumors. Critical to realizing this goal is to establish the mechanisms underlying this sensitivity so that these drug combinations can be prescribed to patients who will gain the greatest benefit. This will also avoid administering drugs to patients unlikely to respond. All the drugs under investigation are either FDA approved or in clinical development so translation to clinical trials will be feasible within a very short time frame.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA117874-06A1
Application #
8499599
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2005-12-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$298,106
Indirect Cost
$113,806
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Sakurikar, Nandini; Thompson, Ruth; Montano, Ryan et al. (2016) A subset of cancer cell lines is acutely sensitive to the Chk1 inhibitor MK-8776 as monotherapy due to CDK2 activation in S phase. Oncotarget 7:1380-94
Sakurikar, Nandini; Eastman, Alan (2015) Will targeting Chk1 have a role in the future of cancer therapy? J Clin Oncol 33:1075-7
Hou, Huagang; Krishnamurthy Nemani, Venkata; Du, Gaixin et al. (2015) Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry. Int J Cancer 136:1688-96
Hou, Huagang; Khan, Nadeem; Lariviere, Jean et al. (2014) Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: a longitudinal study by EPR oximetry using single-probe implantable oxygen sensors. Adv Exp Med Biol 812:97-103
Khan, Nadeem; Hou, Huagang; Hodge, Sassan et al. (2014) Recurrent low-dose chemotherapy to inhibit and oxygenate head and neck tumors. Adv Exp Med Biol 812:105-11
Thompson, Ruth; Eastman, Alan (2013) The cancer therapeutic potential of Chk1 inhibitors: how mechanistic studies impact on clinical trial design. Br J Clin Pharmacol 76:358-69
Montano, Ryan; Thompson, Ruth; Chung, Injae et al. (2013) Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo. BMC Cancer 13:604
Chang, Li-Ju; Eastman, Alan (2012) Differential regulation of p21 (waf1) protein half-life by DNA damage and Nutlin-3 in p53 wild-type tumors and its therapeutic implications. Cancer Biol Ther 13:1047-57
Montano, Ryan; Chung, Injae; Garner, Kristen M et al. (2012) Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. Mol Cancer Ther 11:427-38
Chang, Li-Ju; Eastman, Alan (2012) Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors. Cell Cycle 11:1818-26

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