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

Chan, David; Kaplan, Jason; Gordon, Gary; Desai, Jayesh

doi:10.3390/curroncol28050312

Cited by 14 publications

(11 citation statements)

References 25 publications

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“…The maximum tolerated dose was 4 mg QW with no dose-limiting toxicities in seven evaluable patients, and 6 mg Q2W with 1 dose-limiting toxicity in six evaluable patients (grade 3 diarrhea) 98 . Long-term follow-up of one patient from the phase 1 trial and a second patient enrolled in a compassionate use program reported confirmed partial responses (41 and 60% maximal tumor reduction from baseline) observed after 1.0 and 1.6 years of treatment with AL101, with response durations of 8.6+ and 2.6+ years, respectively 83 .…”

Section: Inhibition Of γ-Secretase In Dtmentioning

confidence: 86%

“…In a phase 1 dose-escalation study of AL101 (NCT01292655 97 ), 94 patients with advanced solid tumors received weekly or bi-weekly intravenous doses of AL101. Of three patients with DT who were enrolled in the study, two experienced confirmed partial responses and one had stable disease as assessed by RECIST v.1.1 criteria 83 , 98 . The maximum tolerated dose was 4 mg QW with no dose-limiting toxicities in seven evaluable patients, and 6 mg Q2W with 1 dose-limiting toxicity in six evaluable patients (grade 3 diarrhea) 98 .…”

Section: Inhibition Of γ-Secretase In Dtmentioning

confidence: 99%

“…Inhibiting the proteolytic activity of γ-secretase prevents the release of the NICD and its translocation to the nucleus-the key step for activation of all downstream effects 70 leading to decreased expression of several Notch target genes, including those in the HES family. Several small-molecule inhibitors of γ-secretase have reported activity in DT in case reports, as well as in several phase 1 and 2 trials [82][83][84][85][86][87] ; two GSIs are in later stage clinical development (Table 1).…”

Section: Inhibition Of γ-Secretase In Dtmentioning

confidence: 99%

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Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition

Federman

2022

npj Precis. Onc.

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Desmoid tumor (DT) is a rare, soft tissue neoplasm associated with an unpredictable clinical course. Although lacking metastatic potential, DT is often locally aggressive and invasive, causing significant morbidity. Both sporadic DT and familial adenomatous polyposis (FAP)-associated DT are linked to constitutive activation of the Wnt signaling pathway with mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene APC, respectively. Cross-talk between the Notch and Wnt pathways, as well as activation of the Notch pathway resulting from dysregulation of the Wnt pathway, suggest a possible therapeutic target for DT. Due to the role γ-secretase plays in Notch signaling through cleavage of the Notch intracellular domain (with subsequent translocation to the nucleus to activate gene transcription), γ-secretase inhibitors (GSIs) have emerged as a potential treatment for DT. Two GSIs, nirogacestat (PF-03084014) and AL102 are in later-stage clinical development; nirogacestat is being evaluated in a phase 3, randomized, placebo-controlled trial while AL102 is being evaluated in a phase 2/3, dose-finding (part A) and placebo-controlled (part B) trial. This review summarizes current understanding of the molecular pathogenesis of DT focusing on dysregulation of the Wnt signaling pathway, crosstalk with the Notch pathway, and the potential therapeutic role for GSIs in DT.

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Section: Inhibition Of γ-Secretase In Dtmentioning

confidence: 86%

Section: Inhibition Of γ-Secretase In Dtmentioning

confidence: 99%

Section: Inhibition Of γ-Secretase In Dtmentioning

confidence: 99%

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Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition

Federman

2022

npj Precis. Onc.

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“…Early studies have reported tumor regression with two other GSIs: AL101 90 and AL102. 91 Given the promising results obtained to date, several clinical trials of GSIs in DTs are underway (Table 2). 89 A Phase 2 trial (ClinicalTrials.gov identifier NCT04195399) is evaluating nirogacestat in patients aged 1-18 years with DT not amenable to surgery.…”

Section: γ-Secretase Inhibitorsmentioning

confidence: 99%

“…Early studies have reported tumor regression with two other GSIs: AL101 90 and AL102 91 . Given the promising results obtained to date, several clinical trials of GSIs in DTs are underway (Table 2).…”

Section: Systemic Control Strategiesmentioning

confidence: 99%

Evolving strategies for management of desmoid tumor

Riedel

Agulnik

2022

Cancer

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Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease course can be unpredictable. Most DTs are sporadic, harboring somatic mutations in the gene that encodes for βcatenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of βcatenin. Pathology review by an expert soft tissue pathologist is critical in making a diagnosis. Magnetic resonance imaging is preferred for most anatomic locations. Surgery, once the standard of care for initial treatment of DT, is associated with a significant risk of recurrence as well as avoidable morbidity because spontaneous regressions are known to occur without treatment. Consequently, active surveillance in conjunction with pain management is now recommended for most patients. Systemic medical treatment of DT has evolved beyond the use of hormone therapy, which is no longer routinely recommended. Current options for medical management include tyrosine kinase inhibitors as well as more conventional cytotoxic chemotherapy (e.g., anthracyclinebased or methotrexate-based regimens). A newer class of agents, γsecretase inhibitors, appears promising, including in patients who fail other therapies, but confirmation in Phase 3 trials is needed. In summary, DTs present challenges to physicians in diagnosis and prognosis, as well as in determining treatment initiation, type, duration, and sequence. Accordingly, evaluation by a multidisciplinary team with expertise in DT and patient-tailored management are essential. As management strategies continue to evolve, further studies will help clarify these issues and optimize outcomes for patients.

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Signaling pathways in the regulation of cancer stem cells and associated targeted therapy

Wang

2022

MedComm

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Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self‐renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well‐established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor‐associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy‐resistant or ‐refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC‐directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC‐directed therapeutics, with a special focus on those with application approval or under clinical evaluation.

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

Cited by 14 publications

References 25 publications

Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition

Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition

Evolving strategies for management of desmoid tumor

Signaling pathways in the regulation of cancer stem cells and associated targeted therapy

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