Repositioned to kill stem cells

Holyoake, Tessa L.; Vetrie, David

doi:10.1038/nature15213

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…Encouraging results have been obtained in patients affected by chronic myeloid leukemia treated with TZDs and imatinib. Leukemia quiescent cells have been eliminated through a mechanism involving TZD-related inhibition of STAT5 expression responsible of stemness maintenance ( 129 – 131 , 133 ). One relevant ongoing clinical phase II trial using PIO (15 mg) as add-on therapy to imatinib has started in July 2009 in patients affected by chronic myelogenous leukemia with residual molecular disease after imatinib monotherapy for more than 2 years (ACTIM EudraCT 2009-011675-79).…”

Section: Ppar-γ Agonists As Antitumor Drugs: Cross Talk With the Igf mentioning

confidence: 99%

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

Vella¹,

Nicolosi

Giuliano

et al. 2017

Front. Endocrinol.

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It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.

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Section: Ppar-γ Agonists As Antitumor Drugs: Cross Talk With the Igf mentioning

confidence: 99%

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

Vella¹,

Nicolosi

Giuliano

et al. 2017

Front. Endocrinol.

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“…These represent a rare population of cells with stem cell‐like characteristics, lurking within treated primary tumor beds and initiating tumors at distant sites, often after long periods of clinical remission . More importantly, they are thought to be resistant to conventional anticancer therapies including chemotherapy and radiotherapy . Sox2 is a key gene encoding a master transcription factor implicated in maintaining the stemness of embryonic stem cells and appears to become reactivated in several human cancers including glioblastoma multiforme, breast cancer, bladder cancer, lung cancer and ovarian cancer .…”

mentioning

confidence: 99%

Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy

Bialkowski

Jeught

Bevers³

et al. 2018

Intl Journal of Cancer

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Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T-cell exhaustion or disrupt the cross-talk between cancer stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a three-arm combination therapy-consisting of an mRNA-based vaccine to induce antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and TGF-β-improves the therapeutic outcome in subcutaneous TC-1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor-specific immunity and simultaneously targeting multiple resistance mechanisms.

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“…The cumulative incidence of molecular response 4.5 significantly increased in patients with the combinational therapies compared to those received imatinib alone. These results suggest a strong potential of using PPAR-γ agonists as sensitizing agents in combination with TKIs, especially through their effects on LSCs [ 95 , 98 , 99 , 100 , 101 , 102 ]. Currently, the combination of pioglitazone and imatinib is under investigation in a prospective randomized trial (NCT02767063).…”

Section: Potential Roles Of Nrs In Chronic Myelogenous Leukemiamentioning

confidence: 99%

Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia

Pan¹,

Chen²

2020

Cells

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The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.

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Repositioned to kill stem cells

Abstract: In most cases of chronic myeloid leukaemia (CML), a daily oral medication rapidly transforms a progressive and ultimately fatal cancer into a chronic, but manageable condition.

Cited by 4 publications

References 7 publications

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy

Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia

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