Safety and efficacy of gamma‐secretase inhibitor nirogacestat (PF‐03084014) in desmoid tumor: Report of four pediatric/young adult cases

Takahashi, Takuto; Prensner, John R.; Robson, Caroline D.; Janeway, Katherine A.; Weigel, Brenda

doi:10.1002/pbc.28636

Cited by 17 publications

(9 citation statements)

References 18 publications

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“…The AXIN2 gene is a direct and the least tissue-specific transcriptional target of the Wnt/β-catenin pathway (44). The TGFB2 gene is not known as a direct Wnt target but has been found to be up-regulated by Wnt stimulation, likely in a tissuedependent way (52)(53)(54). As mentioned, we also find the TGFB2 gene up-regulated in human desmoid tumors (Dataset S2).…”

Section: Medical Sciencessupporting

confidence: 62%

CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping

Naert

Tulkens

Nieuwenhuysen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Cancer precision medicine implies identification of tumor-specific vulnerabilities associated with defined oncogenic pathways. Desmoid tumors are soft-tissue neoplasms strictly driven by Wnt signaling network hyperactivation. Despite this clearly defined genetic etiology and the strict and unique implication of the Wnt/β-catenin pathway, no specific molecular targets for these tumors have been identified. To address this caveat, we developed fast, efficient, and penetrant genetic Xenopus tropicalis desmoid tumor models to identify and characterize drug targets. We used multiplexed CRISPR/Cas9 genome editing in these models to simultaneously target a tumor suppressor gene (apc) and candidate dependency genes. Our methodology CRISPR/Cas9 selection–mediated identification of dependencies (CRISPR-SID) uses calculated deviations between experimentally observed gene editing outcomes and deep-learning–predicted double-strand break repair patterns to identify genes under negative selection during tumorigenesis. This revealed EZH2 and SUZ12, both encoding polycomb repressive complex 2 components, and the transcription factor CREB3L1 as genetic dependencies for desmoid tumors. In vivo EZH2 inhibition by Tazemetostat induced partial regression of established autochthonous tumors. In vitro models of patient desmoid tumor cells revealed a direct effect of Tazemetostat on Wnt pathway activity. CRISPR-SID represents a potent approach for in vivo mapping of tumor vulnerabilities and drug target identification.

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Section: Medical Sciencessupporting

confidence: 62%

CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping

Naert

Tulkens

Nieuwenhuysen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, Tazemetostat treatment in the Xenopus model induced a rapid measurable response. This contrasts with the timelines towards clinical responses of the tyrosine kinase inhibitor sorafenib (median time 9.6 months) and the gamma-secretase inhibitor Nirogacestat (> 8 months) currently available to patients afflicted with desmoid tumors (Gounder et al, 2018;Takahashi et al, 2020). Also, for both latter cases the actual drug target involved in the beneficial clinical outcome in desmoid tumors remains unknown.…”

Section: Discussionmentioning

confidence: 95%

CRISPR-SID: identifying EZH2 as a druggable target for desmoid tumors viain vivodependency mapping

Naert

Tulkens

Nieuwenhuysen

et al. 2019

Preprint

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Identification of true dependencies in cancer is pivotal to the elucidation of novel therapeutic strategies to increase prospects for cancer patients. Unfortunately, in vivo identification of genetic dependencies has long relied on expensive and time-consuming breeding of genetically engineered animal models.Recently, in vitro CRISPR/Cas9 screens provided a new method for rapid and genome-wide identification of genetic dependencies. Nevertheless, genetic dependencies would ideally be identified using in vivo cancer models initiated by clinically relevant oncogenic driver or tumor suppressor insults. Here, we report a new methodology called CRISPR/Cas9-mediated Negative Selection Identification of genetic Dependencies (CRISPR-NSID) that allows in vivo elucidation of cancer cell vulnerabilities in genetic cancer models. The methodology hinges on the fact that for a genetic dependency there is an incapability for recovering tumors carrying biallelic frameshift mutations in this gene. We demonstrate how integrating experimentally determined, or in silico predicted, probabilities of frameshift editing for any given gRNA can be employed to ascertain negative selection pressure on inactivation of a genetic dependency during tumorigenesis. As a proof-of-principle, we use CRISPR-NSID to identify ezh2 and creb3l1 as genetic dependencies in desmoid tumors (desmoid-type fibromatosis) occurring in a Xenopus tropicalis cancer model driven by apc mutations. Bridging CRISPR-NSID to a clinically unmet need, we further demonstrate the promise for EZH2 inhibition as a new therapeutic strategy for desmoid tumors.This study establishes a new methodology for rapid identification of genetic dependencies in monoclonal disorders with wide adaptability to other model systems and organisms.

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“…Grade 3 hypophosphatemia (47%) was reported and was attributed to treatment with nirogacestat [ 18 ]. Among 4 pediatric patients with DT, 3 of whom had tumors harboring APC mutations [ 20 ], 3 patients (1 of whom did not have an APC mutation) had durable benefit with nirogacestat treatment. The fourth patient progressed on therapy after an initial PR.…”

Section: Discussionmentioning

confidence: 99%

“…This leads to decreased expression of a number of Notch target genes, including those in the HES family [ 16 ]. Results from recent clinical trials and case studies have indicated that GSIs have clinical activity in patients with DT [ 17 , 18 , 19 , 20 ]. AL101 and AL102 are structurally similar, potent allosteric small molecule inhibitors of gamma secretase (parenterally and orally administered, respectively) that abrogate activation of all 4 human Notch receptors [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases

Chan

Kaplan²,

Gordon³

et al. 2021

Current Oncology

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Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.

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Safety and efficacy of gamma‐secretase inhibitor nirogacestat (PF‐03084014) in desmoid tumor: Report of four pediatric/young adult cases

Cited by 17 publications

References 18 publications

CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping

CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping

CRISPR-SID: identifying EZH2 as a druggable target for desmoid tumors viain vivodependency mapping

Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases

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