Mechanisms of resistance off NSCLC to interferons

Hasthorpe, Suzanne; Holland, Kerry A.; Nink, Virginia; Lawler, Celine B.; Hertzog, Paul J.

doi:10.3892/ijo.10.5.933

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by observations that in vitro, different components of the IFN response are frequently inactivated in immortalized cells and tumor cells. [45][46][47] In addition, as CBL0137 can act through a number of anticancer mechanisms, including inhibition of the NFκB pathway, activation of the p53 pathway, c-trapping of FACT and induction of an IFN response, 13,[20][21][22] it is possible that the CBL0137-induced inhibition of cancer cell growth is mediated by different mechanisms in different cancer cells. We observed that the antileukemic effect of CBL0137 on the MLL-2 PDX is marked by the absence of cleaved PARP and only a modest decrease in PUMA levels within 24 hr of treatment, in contrast to the significantly increased levels of cleaved PARP, p21 and PUMA in the MLL-6 and MLL-7 PDXs.…”

Section: Discussionmentioning

confidence: 99%

“…[45][46][47] In addition, as CBL0137 can act through a number of anticancer mechanisms, including inhibition of the NFκB pathway, activation of the p53 pathway, c-trapping of FACT and induction of an IFN response, 13,[20][21][22] it is possible that the CBL0137-induced inhibition of cancer cell growth is mediated by different mechanisms in different cancer cells. It is possible that in vitro, the anticancer action of CBL0137 is predominantly mediated through its FACT-dependent action of NFκB pathway inhibition, and not through induction of an IFN response.…”

Section: Cancer Therapy and Preventionmentioning

confidence: 99%

See 1 more Smart Citation

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

Somers

Kosciolek

Bongers

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy‐resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL‐rearranged (MLL‐r) leukemia that can be combined with established chemotherapeutics to decrease treatment‐related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL‐r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL‐r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL‐r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well‐tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL‐r acute myeloid leukemia model and in patient‐derived xenograft models of MLL‐r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL‐r leukemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Cancer Therapy and Preventionmentioning

confidence: 99%

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

Somers

Kosciolek

Bongers

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…IFNs can also regulate the apoptotic machinery by controlling the extrinsic and intrinsic apoptotic pathways (20, 21). Thanks to the deletion of type I IFN genes (22) and the down-regulation of IFN receptors (23, 24) or signaling molecules involved in the IFN cascade, such as STAT1 (25), all these regulatory effects can be bypassed by tumor cells. All these findings can explain the partial failure of IFN treatment used to control cancer cell proliferation in different models.…”

Section: Ifns’ Role In Cancermentioning

confidence: 99%

Role of Type I and II Interferons in Colorectal Cancer and Melanoma

et al. 2017

View full text Add to dashboard Cite

Cancer can be considered an aberrant organ with a hierarchical composition of different cell populations. The tumor microenvironment, including the immune cells and related cytokines, is crucial during all the steps of tumor development. In particular, type I and II interferons (IFNs) are involved in a plethora of mechanisms that regulate immune responses in cancer, thus balancing immune escape versus immune surveillance. IFNs are involved in both the direct and indirect regulation of cancer cell proliferation and metastatic potential. The mutational background of genes involved in IFNs signaling could serve as a prognostic biomarker and a powerful tool to screen cancer patients eligible for checkpoint blocking therapies. We herewith describe the latest findings regarding the contribution of IFNs in colorectal cancer and melanoma by researching their dual role as either tumor promoter or suppressor, in diverse tumor types, and microenvironmental context. We are reporting the most innovative and promising approaches of IFN-based therapies that have achieved considerable outcomes in clinical oncology practice and explain the possible mechanisms responsible for their failure.

show abstract

Antitumour actions of interferons: implications for cancer therapy

2016

View full text Add to dashboard Cite

The interferons (IFNs) are a family of cytokines that protect against disease by direct effects on target cells and by activating immune responses. The production and actions of IFNs are finely tuned to achieve maximal protection and avoid the potential toxicity associated with excessive responses. IFNs are back in the spotlight owing to mounting evidence that is reshaping how we can exploit this pathway therapeutically. As IFNs can be produced by, and act on, both tumour cells and immune cells, understanding this reciprocal interaction will enable the development of improved single-agent or combination therapies that exploit IFN pathways and new 'omics'-based biomarkers to indicate responsive patients.

show abstract

Mechanisms of resistance off NSCLC to interferons

Cited by 3 publications

References 0 publications

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

Role of Type I and II Interferons in Colorectal Cancer and Melanoma

Antitumour actions of interferons: implications for cancer therapy

Contact Info

Product

Resources

About