Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Guimarães, Pedro Pires Goulart; Tan, Mingchee; Tammela, Tuomas; Wu, Katherine; Chung, Amanda; Oberli, Matthias A.; Wang, Karin; Spektor, Roman; Riley, Rachel; Viana, Celso Tarso Rodrigues; Jacks, Tyler; Langer, Robert; Mitchell, Michael J.

doi:10.1016/j.jconrel.2018.09.025

Cited by 40 publications

(21 citation statements)

References 43 publications

(69 reference statements)

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“…We believe it is likely that either the accumulation of specific oncogenic events, or prolonged in vitro culture relieved their WNT dependence, confounding the correlation of TNKSi response and APC/WNT alterations. Indeed, one recent study in lung adenocarcinoma demonstrated that WNT/RSPO-dependent 3D organoid cultures become WNT-independent when cultured in 2D (35). Further, Lord and colleagues recently proposed that activating Kras mutations may correlate with resistance to TNKS inhibitors (36).…”

Section: Discussionmentioning

confidence: 99%

Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

et al. 2019

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The majority of colorectal cancers (CRCs) show hyperactivated WNT signaling due to inactivating mutations in the APC tumor suppressor. Genetically restoring Apc suppresses WNT and induces rapid and sustained tumor regression, implying that re-engaging this endogenous tumor suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that Tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the Mutation Cluster Region (MCR) region physically engage the destruction complex and suppress the WNT transcriptional program, while early APC truncations (i.e. Apc Min) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response.

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Section: Discussionmentioning

confidence: 99%

Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

et al. 2019

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“…Long-term treatment with WNT974 can cause intestinal and bone damage in mice (22,23). To enable potent and sustained WNT suppression in tumor cells without effects on surrounding tissues, we used the regulatable shApc model, whereby withdrawal of dox from chow drives rapid APC restoration and potent WNT pathway suppression (10,11).…”

Section: The In Vivo Tumor Microenvironment Is Sufficient To Prime Cementioning

confidence: 99%

Lineage reversion drives WNT independence in intestinal cancer

Han

Goswami

et al. 2020

Preprint

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The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNTindependent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFb exposure drives YAP/ TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work delineates genetic and microenvironmental factors that drive WNT inhibitor resistance, identifies a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.

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“…The earliest uses of supramolecular macrocycles in drug delivery were in the context of excipients which functioned primarily by improving the solubility and formulation stability of a diverse array of hydrophobic drugs and increasing cell permeability for charged species 15-17. In addition, there are examples using inclusion within supramolecular macrocycles as a method to mitigate the toxicity of a drug 18. These uses are typically characterized by equilibrium-governed interactions between a drug guest and a hydrophilic macrocycle host.…”

Section: Introductionmentioning

confidence: 99%

Integrating Stimuli-Responsive Properties in Host-Guest Supramolecular Drug Delivery Systems

2019

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Host-guest motifs are likely the most recognizable manifestation of supramolecular chemistry. These complexes are characterized by the organization of small molecules on the basis of preferential association of a guest within the portal of a host. In the context of their therapeutic use, the primary application of these complexes has been as excipients which enhance the solubility or improve the stability of drug formulations, primarily in a vial. However, there may be opportunities to go significantly beyond such a role and leverage key features of the affinity, specificity, and dynamics of the interaction itself toward “smarter” therapeutic designs. One approach in this regard would seek stimuli-responsive host-guest recognition, wherein a complex forms in a manner that is sensitive to, or can be governed by, externally applied triggers, disease-specific proteins and analytes, or the presence of a competing guest. This review will highlight the general and phenomenological design considerations governing host-guest recognition and the specific types of chemistry which have been used and are available for different applications. Finally, a discussion of the molecular engineering and design approaches which enable sensitivity to a variety of different stimuli are highlighted. Ultimately, these molecular-scale approaches offer an assortment of new chemistry and material design tools toward improving precision in drug delivery.

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Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Cited by 40 publications

References 43 publications

Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

Lineage reversion drives WNT independence in intestinal cancer

Integrating Stimuli-Responsive Properties in Host-Guest Supramolecular Drug Delivery Systems

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