Cancer prevention IIDrug Development for Cancer Chemoprevention: Focus on Molecular Targets
Section snippets
Targeting the Estrogen Receptor
Among solid tumors, the treatment of breast cancer with targeted drugs has a long record benchmarked by the initial US FDA approval of tamoxifen for metastatic breast cancer treatment in 1977. Long-term experience with tamoxifen across the spectrum of breast oncogenesis from metastatic disease to pre-malignancy has been invaluable for the translation of data from tamoxifen clinical trials in support of an approved cancer prevention indication. It is consequently instructive to review the
Targeting the Androgen Receptor
As in the treatment setting, the potential effectiveness of AIs in the prevention setting remains a consequence of estrogen deprivation, an indirect but effective approach to limiting the function of the ER. Although the adverse events from drugs used in androgen receptor blockade for prostate cancer treatment did not allow androgen receptor blockers to be used in prostate cancer prevention,43 the androgen receptor still remains a target of testosterone deprivation just as estrogen deprivation
Cyclooxygenase, Inflammation, and Colorectal Cancer
The association linking NSAIDs with reduced colorectal cancer risk is much stronger than the association for NSAIDs and breast cancer. In a systematic review prepared for the US Preventive Services Task Force (PSTF), observational evidence from cohort studies was summarized as showing that the use of NSAIDs was associated with an approximate 40% reduction in colorectal cancer incidence.47 In this same report, observational evidence for the association between NSAIDs and colorectal adenomas was
Epidermal Growth Factor Receptor and Other Targets
Of the targets listed in Table 1, much of the work of targeted cancer prevention has focused on the ER and the androgen receptor with spin-off activities implicating related pathways mediated by enzymes such as aromatase, 5α-reductase, and COX. For these targets, a long history of effort has generated a large reservoir of preclinical and clinical experience, to the point that large, phase III prevention trials with a cancer incidence endpoint were facilitated. Extended experience with some of
Targeting Molecular Risk Signatures for Prevention
Although treatment trials have played a central role in identifying cancer prevention targets, it is critically useful to appreciate two important but related differences in the clinical investigation approach used in treatment versus prevention. First, every individual enrolled in a treatment trial has a diagnosis of cancer, and this point allows for testing the tumor tissue for the drug target of interest. This aspect of lesion availability is largely responsible for the more manageable
Risk Signatures and DNA Repair
One of the frustrations in conducting cancer prevention trials is the dilemma posed by individuals who are known to be at high risk of developing cancer without visually detectable tissue abnormalities (eg, metaplasia and dysplasia). Lacking tissue abnormalities that can be identified and followed as intervention response markers complicates the assessment of eligibility for prevention trials. In the absence of abnormal histological morphology, it now seems that prevention science is on the
Screening Prevention Drugs for Targeted Activity
In addition to the need for tissue-based molecular definition of cancer risk, another obstacle to developing cancer prevention agents is the plethora of leads that have acquired a modicum of plausibility for testing as prevention interventions. For example, in the category of flavonoid compounds (flavonols, flavones, anthocyanidins, catechins, flavanones and isoflavones), more than 5,000 compounds have been identified.79 Using traditional methods and approaches,80 it would easily be possible to
Conclusion
The focus of this review has been the pharmacologic manipulation of targets within epithelial tumor cells and the potential of those targets to mediate suppression and elimination of premalignant cells in human tissue. Early results suggest that molecular risk signatures may allow the investigational evaluation of premalignant tissue for risk reduction secondary to clinical intervention in a way that is analogous to the measurement of tumor shrinkage in response to treatment. Improved
References (112)
Exemestane, a new steroidal aromatase inhibitor of clinical relevance
Biochim Biophys Acta
(2002)- et al.
Tamoxifen and contralateral breast cancer
Lancet
(1985) - et al.
The pharmacology of letrozole
J Steroid Biochem Mol Biol
(2003) - et al.
Aromatase and in situ estrogen production in DCIS (ductal carcinoma in situ) of human breast
J Steroid Biochem Mol Biol
(2010) The endocrine prevention of breast cancer
Best Pract Res Clin Endocrinol Metab
(2008)- et al.
Translational studies on aromatase, cyclooxygenases, and enzyme inhibitors in breast cancer
J Steroid Biochem Mol Biol
(2005) - et al.
Chemoprevention of prostate cancer
Urology
(1994) - et al.
Colorectal cancer prevention: is an ounce of prevention worth a pound of cure?
Semin Oncol
(2005) - et al.
A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas
Gastroenterology
(2006) The management of intraductal papillary mucinous neoplasms of the pancreas
Surg Oncol Clin N Am
(2010)
Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia
Gastroenterology
Ten genes for inherited breast cancer
Cancer Cell
Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women
Am J Clin Nutr
Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways
Am J Pathol
Potent and selective inhibition of the tumor marker AKR1B10 by bisdemethoxycurcumin: probing the active site of the enzyme with molecular modeling and site-directed mutagenesis
Biochem Biophys Res Commun
Demethoxycurcumin induces Bcl-2 mediated G2/M arrest and apoptosis in human glioma U87 cells
Biochem Biophys Res Commun
Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins
Cancer Lett
Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies
Biochem Pharmacol
Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids
Mol Pharmacol
DNA and RNA as new binding targets of green tea catechins
J Biol Chem
Karnofsky Award lectureImatinib as a paradigm of targeted therapies
J Clin Oncol
From the FDA
JAMA
Phase II and III clinical trials of toremifene for metastatic breast cancer
Oncology (Williston Park)
Fulvestrant in postmenopausal women with advanced breast cancer
Clin Cancer Res
Use of aromatase inhibitors in postmenopausal women with advanced breast cancer
J Surg Oncol
Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer
Clin Cancer Res
Drug update: trastuzumab: anti-HER2 antibody for treatment of metastatic breast cancer
Cancer Pract
Lapatinib
Nat Rev Drug Discov
Flutamide: an antiandrogen for advanced prostate cancer
Drug Intell Clin Pharm
Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development
Prostate
Cetuximab
Nat Rev Drug Discov
FDA review of a panitumumab (Vectibix) clinical trial for first-line treatment of metastatic colorectal cancer
Oncologist
Gefitinib
Nat Rev Drug Discov
Sorafenib and sunitinib
Oncologist
Temsirolimus
Nat Rev Drug Discov
Everolimus
Nat Rev Drug Discov
Steroid hormone receptors in breast cancer management
Breast Cancer Res Treat
The Breast Cancer Continuum: insights from the tamoxifen trials impact future drug development strategies
Ann N Y Acad Sci
Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study
J Natl Cancer Inst
Effects of tamoxifen on benign breast disease in women at high risk for breast cancer
J Natl Cancer Inst
Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study
J Natl Cancer Inst
The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trialMultiple Outcomes of Raloxifene Evaluation
JAMA
Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene
J Natl Cancer Inst
Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women
N Engl J Med
Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial
JAMA
Epitope characterization of an aromatase monoclonal antibody suitable for the assessment of intratumoral aromatase activity
PLoS One
Update on the use of aromatase inhibitors in breast cancer
Expert Opin Pharmacother
Intratumoral estrogen disposition in breast cancer
Clin Cancer Res
In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer
BMC Cancer
Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment
Endocr Relat Cancer
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2020, Translational OncologyCitation Excerpt :Smurf1 is highly expressed in multiple cancers, including CRC [4], ovarian cancer [5], and breast cancer [6]. It plays a critical role in the occurrence and development of multiple tumors by targeting diverse substrates such as RhoA [7], DAB2IP [8], and ARHGP26 [5] for ubiquitin-dependent degradation and regulates tumor cell growth and metastasis. However, it is significantly unclear if Smurf1 regulates the sensitivity of cancer cells to chemotherapeutic drugs.
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2015, Drug Discovery TodayCitation Excerpt :Indeed, the rational design of HIV-protease inhibitors provided a benchmark for establishing relatively safe and effective therapeutic strategy [17]. Rational design assumes one has accurate knowledge of the most effective targets and can implement this to design ideal medicines [18] and could eliminate the serendipity often associated with phenotypic strategies that conveyed many successful medicines [19]. Indeed, a recent study emphasizes the success of phenotypic approaches as compared with target-based design [20].
Tumour progression and cancer-induced pain: A role for protease-activated receptor-2?
2014, International Journal of Biochemistry and Cell BiologyCitation Excerpt :Due to the complex nature of the pathology of cancer, the search for therapeutic targets continues. Small molecule inhibitors of key receptors or enzyme binding sites, and monoclonal antibodies that recognise key receptors and their ligands have been a focus in the development of novel chemotherapeutic agents in recent years (Johnson and Brown, 2010). PAR2 is of great interest in this context with the availability of synthetic agonists and antagonists (Yau et al., 2013).
Cancer Prevention, Screening, and Early Detection
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Deceased, August 19, 2010.