Resistance to Chemotherapy and Molecularly Targeted Therapies: Rationale for Combination Therapy in Malignant Melanoma

Wu, Sing-Yung; Singh, Rakesh K.

doi:10.2174/156652411800615153

Cited by 39 publications

(29 citation statements)

References 69 publications

(73 reference statements)

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“…While initially effective, the formation of tumors resistant to this agent is likely to occur with other immune system modulators (39). These observations underscore the plasticity of melanoma in acquiring resistance to targeted chemotherapeutic or immune modulating agents and the need to identify agents targeting multiple important pathways involved in melanoma to circumvent the development of resistance (40, 41). This may be achievable through the use of drug cocktails or a single drug simultaneously inhibiting multiple key signaling pathways implicated in melanoma, which is detailed in this report through the discovery of leelamine.…”

Section: Discussionmentioning

confidence: 98%

“…The consequence is retardation of melanoma xenograft tumor development without affecting animal weight or organ function. Targeting multiple key pathways involved in melanoma by combining existing agents could also help prevent recurrent resistant disease (40, 41). Preclinical and clinical studies have tested whether combining Zelboraf with agents targeting the PI3K pathway or MEK1/2 would cooperatively inhibit melanoma tumor growth (47).…”

Section: Discussionmentioning

confidence: 99%

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Targeting Multiple Key Signaling Pathways in Melanoma Using Leelamine

Gowda

Madhunapantula²,

Kuzu

et al. 2014

Molecular Cancer Therapeutics

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Melanoma is a highly drug resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The PI3 kinase (PI3K), MAP kinase (MAPK) and STAT3 pathways are constitutively activated in 50–70% of melanomas promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK and STAT3 cascades, a natural product library was screened to identifying leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC50 values of 2 and 9.3 µmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 µmol/L by 40–80% and longer exposure increased apoptosis 600% through a mechanism detailed in the article in the current issue of this journal by Kuzu OF et al. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and, consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Targeting Multiple Key Signaling Pathways in Melanoma Using Leelamine

Gowda

Madhunapantula²,

Kuzu

et al. 2014

Molecular Cancer Therapeutics

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show abstract

“…Alkylating agents, such as dacarbazine and its prodrug temozolomide, were approved in 1974 by the US FDA; however, the responses to this treatment were very short and less than 5% of patients could achieve a complete response (30, 31). Moreover, chemotherapy treatments were reported to be associated with severe side effects (32, 33) and a very rapid tumor relapse (34). In 1998, the US FDA approved IL-2 for the treatment of metastatic melanoma, based on clinical observations demonstrating sustained remissions in approximately 5–10% of patients (35).…”

Section: Current Therapies For Advanced Melanomamentioning

confidence: 99%

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to ERβ have been identified. These phytoestrogens decrease the proliferation of melanoma cells. Importantly, these effects are unrelated to the oncogenic mutations of melanomas, suggesting that, in addition to their ERβ activating function, these compounds might impair melanoma development through additional mechanisms. A better identification of the role of ERβ in melanoma development will help increase the therapeutic options for this aggressive pathology.

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“…Similarly, gefitinib was shown to increase the efficacy of taxanes in breast cancer by inhibiting the EGFR-Akt signaling pathway (2). Indeed, many of these combinations are further rationalized by the feedback upregulation of these molecular targets following treatment with cytotoxic chemotherapy (3). A critical question that therefore arises is whether the sequence of administration of the agents can potentially impact the antitumor outcome?…”

Section: Introductionmentioning

confidence: 99%

Sequential Application of a Cytotoxic Nanoparticle and a PI3K Inhibitor Enhances Antitumor Efficacy

et al. 2014

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Nanomedicines that preferentially deploy cytotoxic agents to tumors, and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited pro-survival signaling via an epidermal growth factor receptor-phosphatidylinositol 3 kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacological inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer.

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Resistance to Chemotherapy and Molecularly Targeted Therapies: Rationale for Combination Therapy in Malignant Melanoma

Cited by 39 publications

References 69 publications

Targeting Multiple Key Signaling Pathways in Melanoma Using Leelamine

Targeting Multiple Key Signaling Pathways in Melanoma Using Leelamine

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Sequential Application of a Cytotoxic Nanoparticle and a PI3K Inhibitor Enhances Antitumor Efficacy

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