Cancer
Inventors
GREENFIELD, SUSAN ADELE • TU, Henry • MORRILL, Paul • GARCIA-RATES, Sara • Pepper, Chris • Fegan, Chris
Assignees
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Publication Number
US-11287416-B2
Publication Date
2022-03-29
Expiration Date
Abstract
The invention relates to cancer, and in particular to novel pharmaceutical compositions, therapies and methods for treating, preventing or ameliorating cancer, and especially metastatic disease. The invention also relates to diagnostic and prognostic methods for cancer and metastatic disease, and biomarkers for these conditions.
Core Innovation
The invention relates to cancer and metastatic disease using the toxic acetylcholinesterase-derived peptide T14 (SEQ ID No: 3), including a variant thereof embedded from tailed acetylcholinesterase (T-AChE). The concept centers on detecting and targeting endogenous T14 (SEQ ID No: 3) to diagnose metastatic disease and to inform treating metastatic disease with an effective amount of a treatment for metastatic disease.
The document describes the peptide as binding an allosteric site on the b17 nicotinic receptor, enhancing ligand-induced Ca2+ influx. This is linked to mitochondrial dysfunction, oxidative phosphorylation-related electron leakage, free-radical formation, membrane destabilization, and ultimately cell death.
The document also describes substituted inhibitor compounds for a peptidomimetic T14 scaffold, including related Tri02 and Tri04, and Tri02/Tri04-like compounds, defined by Formula (I) / (Ia) and related specific formulas. The disclosure provides general substituent definitions for R groups and preferred substructures, and includes explicit example chemical structures corresponding to the stated formulas.
Claims Coverage
The provided claim set includes two independent claims focused on a diagnosis-and-treatment workflow for metastatic disease based on detecting endogenous material corresponding to SEQ ID No: 3, followed by administering an effective amount of a metastatic-disease treatment. The inventive features across the independent claims are the specific detection target definitions and the associated diagnosis-triggered administration of metastatic disease treatment.
Detecting an endogenous peptide with identity threshold
Obtaining a sample and detecting, in the sample, an endogenous peptide of SEQ ID No: 3, or a variant thereof having at least 90% sequence identity to SEQ ID No: 3.
Diagnosis based on detecting SEQ ID No: 3 peptide and administering metastatic disease treatment
Diagnosing the individual with metastatic disease when the presence of the endogenous peptide of SEQ ID No: 3, or a variant thereof having at least 90% sequence identity to SEQ ID No: 3, is detected in the sample; and administering an effective amount of a treatment for metastatic disease to the diagnosed individual.
Detecting an endogenous antigen consisting of SEQ ID No: 3
Obtaining a sample and detecting the presence of an endogenous antigen consisting of SEQ ID No: 3 in the sample.
Diagnosis based on detecting SEQ ID No: 3 antigen and administering metastatic disease treatment
Diagnosing the individual with metastatic disease when the presence of the endogenous antigen in the sample is detected; and administering an effective amount of a treatment for metastatic disease to the diagnosed individual.
Across the independent claims, the core claim coverage centers on using a patient sample to detect a SEQ ID No: 3-defined endogenous target, diagnosing metastatic disease when that target is detected, and then administering an effective amount of a metastatic disease treatment to the diagnosed individual.
Stated Advantages
Allows diagnosing metastatic disease, or a pre-disposition thereto, based on detecting endogenous SEQ ID No: 3 material.
Enables administering an effective amount of a treatment for metastatic disease to the diagnosed individual.
The document reports prognostic significance for serum T14 quantification using Kaplan-Meier estimate results, including hazard ratio, p value, and median TTFT.
The document states that antibody and peptidomimetics can treat cancer/metastasis.
The document states that low blood T14 indicates worse prognosis and longer time to first treatment.
Documented Applications
Diagnostic and therapeutic method for an individual who suffers from metastatic disease, or a pre-disposition thereto, involving detecting endogenous SEQ ID No: 3 material and treating the diagnosed individual for metastatic disease.
Prognostic evaluation in CLL serum cohorts using serum T14 quantification with Kaplan-Meier estimate reporting.
Detection workflows for generating T14-linked biomarker measurements using ELISA and Western blot and detecting T14-linked targets including AChE, b5 nicotinic acetylcholine receptor, and CD44.
Therapeutic modulation studies using peptidomimetic T14 inhibitors Tri02 and Tri04 to inhibit T14 activity in cell-based assays and to modulate brain-slice VSDI network activity.
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