Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma

Dubrovska, Anna; Elliott, Jimmy; Salamone, Richard J.; Kim, Sungeun; Aimone, Lindsey J.; Walker, John R.; Watson, James P.; Maira, Sauveur‐Michel; García‐Echeverría, Carlos; Cho, Charles Y.; Reddy, Venkateshwar A.; Schultz, Peter G.

doi:10.1158/1078-0432.ccr-10-1601

Cited by 103 publications

(133 citation statements)

References 44 publications

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“…This will allow therapies to be made swiftly available for all suitable candidates. We can only hope that novel and safe targeted anticancer agents will come from these drug discovery efforts [171][172][173][174][175][176][177][178] .…”

Section: Resultsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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Section: Resultsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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“…Vice versa, nonCSCs in colon cancers can protect CSCs from the toxicity of chemotherapeutic drugs [148]. These discussions illustrate the potential benefit of combinatorial targeting of both tumor-initiating and differentiated tumor cells [149]. By simultaneously targeting the tumorigenic and non-tumorigenic populations, both cancer cell heterogeneity and plasticity can be overcome ( Figure 5C-5D).…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 93%

Understanding cancer stem cell heterogeneity and plasticity

2012

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Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.

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“…Taken together, these observations highlight the benefit of targeting undifferentiated CSCs as well as differentiated non-CSCs. By synchronously targeting tumorigenic and non-tumorigenic cells, cancer cell heterogeneity and plasticity could theoretically be eradicated (63). In clinical treatment, non-tumorigenic tumor cells are treated relatively easily by most standard-of-care therapies, whereas the current obstacle is to identify novel therapeutic agents that specifically target undifferentiated or dormant CSCs, which should be identifiable by exploiting CSC-specific phenotypic or genetic features.…”

Section: Resultsmentioning

confidence: 99%

Targeted therapy against cancer stem cells

Yang

Rycaj

2015

Oncology Letters

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Abstract. Research into cancer stem cells (CSCs), which have the ability to self-renew and give rise to more mature (differentiated) cancer cells, and which may be the cells responsible for the overall organization of a tumor, has progressed rapidly and concomitantly with recent advances in studies of normal tissue stem cells. CSCs have been reported in a wide spectrum of human tumors. Like normal tissue stem cells, CSCs similarly exhibit significant phenotypic and functional heterogeneity. The ability of CSCs to self-renew results in the immortality of malignant cells at the population level, whereas the ability of CSCs to differentiate, either fully or partially, generates the cellular hierarchy and heterogeneity commonly observed in solid tumors. CSCs also appear to have maximized their pro-survival mechanisms leading to their relative resistance to anti-cancer therapies and subsequent relapse. Studies in animal models of human cancers have also provided insight into the heterogeneity and characteristics of CSCs, helping to establish a platform for the development of novel targeted therapies against specific CSCs. In the present study, we briefly review the most recent progress in dissecting CSC heterogeneity and targeting CSCs in various human tumor systems. We also highlight a few examples of CSC-targeted drug development and clinical trials, with the ultimate aim of developing more effective therapeutic regimens that are capable of preventing tumor recurrence and metastasis. IntroductionThe etiology of cancer development and the molecular mechanisms underlying conventional therapy-resistant progression, metastasis and recurrence are poorly understood, resulting in numerous patients who still fail therapy. Cancer is recognized as a heterogeneous disease, an intrinsic attribute that contributes to therapy failure. Emerging evidence from a number of tumor systems has revealed the existence of distinct subpopulations of stem-like cancer cells, termed cancer stem cells (CSCs), that possess clonal long-term repopulation and self-renewal capacities. Theories suggest that both genetic and CSC models of cancer contribute to this tumor heterogeneity. With stemness as a guiding principle, data generated from advanced genome sequencing, epigenetics and the influences of non-tumor cell elements in the tumor microenvironment could potentially be combined in order to reveal the underlying mechanisms of tumor heterogeneity (1). As a fraction of this heterogeneous population, CSCs are inherently resistant to cytotoxic chemotherapy and radiation, and evidence has linked stemness to prognosis and therapy failure (2). This suggests that specifically identifying how CSC involvement is linked to tumor initiation, progression, metastasis and therapy resistance may lead to a more perceptive approach of developing therapeutics to target this cell population. Despite the vast complexity observed within a tumor, there are fundamental attributes of CSCs that may be exploited in drug development. A number of potential CSC therapeutic...

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Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma

Cited by 103 publications

References 44 publications

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Understanding cancer stem cell heterogeneity and plasticity

Targeted therapy against cancer stem cells

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