Targeting pan-essential genes in cancer: Challenges and opportunities

Chang, Liang; Ruiz, Paloma Gallar; Ito, Takahiro; Sellers, William R.

doi:10.1016/j.ccell.2020.12.008

Cited by 116 publications

(104 citation statements)

References 118 publications

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“…Another example is the mucositis and glucose deregulation observed with everolimus, which produces treatment discontinuations [ 111 ]. In this context, it is expected that strategies targeting pan-essential genes will be toxic, having an inverse therapeutic index [ 112 , 113 ]. Nano-vectorization is a potential approach to improve their delivery and reduce their toxicity.…”

Section: Polymeric Nps In Clinical Investigationsmentioning

confidence: 99%

Polyester Polymeric Nanoparticles as Platforms in the Development of Novel Nanomedicines for Cancer Treatment

Niza

Ocaña

Castro‐Osma

et al. 2021

Cancers

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Many therapeutic agents have failed in their clinical development, due to the toxic effects associated with non-transformed tissues. In this context, nanotechnology has been exploited to overcome such limitations, and also improve navigation across biological barriers. Amongst the many materials used in nanomedicine, with promising properties as therapeutic carriers, the following one stands out: biodegradable and biocompatible polymers. Polymeric nanoparticles are ideal candidates for drug delivery, given the versatility of raw materials and their feasibility in large-scale production. Furthermore, polymeric nanoparticles show great potential for easy surface modifications to optimize pharmacokinetics, including the half-life in circulation and targeted tissue delivery. Herein, we provide an overview of the current applications of polymeric nanoparticles as platforms in the development of novel nanomedicines for cancer treatment. In particular, we will focus on the raw materials that are widely used for polymeric nanoparticle generation, current methods for formulation, mechanism of action, and clinical investigations.

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Section: Polymeric Nps In Clinical Investigationsmentioning

confidence: 99%

Polyester Polymeric Nanoparticles as Platforms in the Development of Novel Nanomedicines for Cancer Treatment

Niza

Ocaña

Castro‐Osma

et al. 2021

Cancers

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“…This demonstrates how understanding mutational signature mechanisms may lead directly to therapeutic insights. Notably, ATR is a ubiquitously essential gene required for survival of both normal and cancer cells, and its inhibition may cause toxicity to normal cells [44]. Thus, careful use of ATR inhibitors in APOBEC-positive cancers, including chemotherapy-like intermittent dosage rather than constant daily dosage, may be needed to achieve a successful therapeutic index for these patients [44].…”

Section: Trends In Geneticsmentioning

confidence: 99%

“…Notably, ATR is a ubiquitously essential gene required for survival of both normal and cancer cells, and its inhibition may cause toxicity to normal cells [44]. Thus, careful use of ATR inhibitors in APOBEC-positive cancers, including chemotherapy-like intermittent dosage rather than constant daily dosage, may be needed to achieve a successful therapeutic index for these patients [44]. Furthermore, APOBEC activity may be intermittent [18,45], suggesting that only tumors with current APOBEC activity may respond to ATR inhibition.…”

Section: Trends In Geneticsmentioning

confidence: 99%

Therapeutic and prognostic insights from the analysis of cancer mutational signatures

2022

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The somatic mutations in each cancer genome are caused by multiple mutational processes, each of which leaves a characteristic imprint (or 'signature'), potentially caused by specific etiologies or exposures. Deconvolution of these signatures offers a glimpse into the evolutionary history of individual tumors. Recent work has shown that mutational signatures may also yield therapeutic and prognostic insights, including the identification of cell-intrinsic signatures as biomarkers of drug response and prognosis. For example, mutational signatures indicating homologous recombination deficiency are associated with poly(ADP)ribose polymerase (PARP) inhibitor sensitivity, whereas APOBEC-associated signatures are associated with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitor sensitivity. Furthermore, therapy-induced mutational signatures implicated in cancer progression have also been uncovered, including the identification of thiopurine-induced TP53 mutations in leukemia. In this review, we explore the various ways mutational signatures can reveal new therapeutic and prognostic insights, thus extending their traditional role in identifying disease etiology. HighlightsMutational signatures have revolutionized our understanding of cancer etiology by identifying biological processes underlying somatic mutagenesis.

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“…All anti-cancer therapeutics principally rely on the selective targeting and destruction of tumour cells over normal cells, known as the therapeutic index. Understanding the differences in the threshold at which cancer cells undergo ferroptosis compared to normal cells is vital for the clinical deployment of ferroptosis inducers, to both mitigate unwanted toxicities and maximise therapeutic benefit [ 23 ]. Ferroptosis inducers could be used to leverage the increased levels of oxidative stress and iron in cancer cells to drive their therapeutic index ( Figure 3 A).…”

Section: Therapeutic Index For Ferroptosismentioning

confidence: 99%

Opportunities for Ferroptosis in Cancer Therapy

2021

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A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis.

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Targeting pan-essential genes in cancer: Challenges and opportunities

Cited by 116 publications

References 118 publications

Polyester Polymeric Nanoparticles as Platforms in the Development of Novel Nanomedicines for Cancer Treatment

Polyester Polymeric Nanoparticles as Platforms in the Development of Novel Nanomedicines for Cancer Treatment

Therapeutic and prognostic insights from the analysis of cancer mutational signatures

Opportunities for Ferroptosis in Cancer Therapy

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