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Am J Transl Res 2011;3(4):434-444
Review Article
Emerging drug discovery approaches for selective targeting of
“precursor” metastatic breast cancer cells: Highlights and
perspectives
Moulay A. Alaoui-Jamali, Krikor Bijian, Gerald Batist
Lady Davis Institute for Medical Research and Segal Cancer Center, Jewish General Hospital, Departments of
Medicine, Oncology, and Pharmacology and Therapeutics, McGill University, Montreal, Qc H3T 1E2, Canada.
Received July 30, 2011; accepted August 16, 2011; Epub September 8, 2011; Published October 31, 2011
Abstract: Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among
women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease,
at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts
adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with
some patients sustaining a recurrence within months after diagnosis, even during adjuvant treatments, while
others can experience recurrence years or decades after initial diagnosis. To date, clinically approved
therapeutics yielded marginal benefits for patients with systemic metastatic breast disease, since despite high
clinical responses to various therapies, the patients virtually always become resistant and tumor relapses.
Molecular profiling studies established that breast cancer is highly heterogeneous and encompasses diverse
histological and molecular subtypes with distinct biological and clinical implications in particular in relation to the
incidence of progression to metastasis. The latter has been recognized to result from late genetic events during
the multistep progression proposed by the dominant theory of carcinogenesis. However there is evidence that the
dissemination of primary cancer can also be initiated at a very early stage of cancer development, originating from
rare cell variants, possibly cancer stem-like cells (CSC), with invasive potential. These precursor metastatic
cancer cells with stem-like properties are defined by their ability to self-renew and to regenerate cell variants,
which have high plasticity and intrinsic invasive properties required for dissemination and tropism toward specific
organs. Equally relevant to the CSC hypothesis for metastasis formation is the epithelial-mesenchymal transition
(EMT) process, which is critical for the acquisition of cancer cell invasive behavior and for selection/gain of CSC
properties. These exciting concepts have led to the formulation of various approaches for targeting precursor
metastasis cells, and these have taken on greater priority in therapeutic drug discovery research by both
academia and pharmaceuticals. In this review, we focus on current efforts in medicinal chemistry to develop
small molecules able to target precursor metastatic cells via interference with the CSC/EMT differentiation
program, self-renewal, and survival. It is not meant to be comprehensive and the reader is referred to selected
reviews that provide coverage of related basic aspects. Rather, emphasis is given to promising molecules with
CSC/EMT signaling at the preclinical stage and in clinical trials that are paving the way to new generations of anti-
metastasis drugs. (AJTR1107006).
Keywords: Breast cancer, metastasis, cancer stem cells, EMT, experimental therapy
Full Text PDF
Address all correspondence to:
M. Alaoui-Jamali
Lady Davis Institute for Medical Research and Segal Cancer Center, Room E534
Jewish General Hospital, Departments of Medicine and Oncology,
McGill University, Montreal, Canada
E-mail: moulay.alaoui-jamali@mcgill.ca
Review Article
Emerging drug discovery approaches for selective targeting of
“precursor” metastatic breast cancer cells: Highlights and
perspectives
Moulay A. Alaoui-Jamali, Krikor Bijian, Gerald Batist
Lady Davis Institute for Medical Research and Segal Cancer Center, Jewish General Hospital, Departments of
Medicine, Oncology, and Pharmacology and Therapeutics, McGill University, Montreal, Qc H3T 1E2, Canada.
Received July 30, 2011; accepted August 16, 2011; Epub September 8, 2011; Published October 31, 2011
Abstract: Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among
women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease,
at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts
adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with
some patients sustaining a recurrence within months after diagnosis, even during adjuvant treatments, while
others can experience recurrence years or decades after initial diagnosis. To date, clinically approved
therapeutics yielded marginal benefits for patients with systemic metastatic breast disease, since despite high
clinical responses to various therapies, the patients virtually always become resistant and tumor relapses.
Molecular profiling studies established that breast cancer is highly heterogeneous and encompasses diverse
histological and molecular subtypes with distinct biological and clinical implications in particular in relation to the
incidence of progression to metastasis. The latter has been recognized to result from late genetic events during
the multistep progression proposed by the dominant theory of carcinogenesis. However there is evidence that the
dissemination of primary cancer can also be initiated at a very early stage of cancer development, originating from
rare cell variants, possibly cancer stem-like cells (CSC), with invasive potential. These precursor metastatic
cancer cells with stem-like properties are defined by their ability to self-renew and to regenerate cell variants,
which have high plasticity and intrinsic invasive properties required for dissemination and tropism toward specific
organs. Equally relevant to the CSC hypothesis for metastasis formation is the epithelial-mesenchymal transition
(EMT) process, which is critical for the acquisition of cancer cell invasive behavior and for selection/gain of CSC
properties. These exciting concepts have led to the formulation of various approaches for targeting precursor
metastasis cells, and these have taken on greater priority in therapeutic drug discovery research by both
academia and pharmaceuticals. In this review, we focus on current efforts in medicinal chemistry to develop
small molecules able to target precursor metastatic cells via interference with the CSC/EMT differentiation
program, self-renewal, and survival. It is not meant to be comprehensive and the reader is referred to selected
reviews that provide coverage of related basic aspects. Rather, emphasis is given to promising molecules with
CSC/EMT signaling at the preclinical stage and in clinical trials that are paving the way to new generations of anti-
metastasis drugs. (AJTR1107006).
Keywords: Breast cancer, metastasis, cancer stem cells, EMT, experimental therapy
Full Text PDF
Address all correspondence to:
M. Alaoui-Jamali
Lady Davis Institute for Medical Research and Segal Cancer Center, Room E534
Jewish General Hospital, Departments of Medicine and Oncology,
McGill University, Montreal, Canada
E-mail: moulay.alaoui-jamali@mcgill.ca
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