JP-2022500464-A5 -

Dates

Publication Date

20230511

Application Date

20190911

Description

Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62/729,959, filed on 11 September 2018, the entire contents of which are incorporated herein by reference. This invention relates to the field of cancer diagnosis and treatment, and more particularly to the treatment, diagnosis, and staging of cancer, in particular cancers that overexpress human epidermal growth factor (or human epidermal growth factor/human epidermal growth factor) receptor 2 protein (HER2+), and to the use of compounds for treating, diagnosing, and staging cancer. The present invention provides methods for inhibiting the growth of HER2+ tumors, inhibiting the growth of HER2+ tumor cells, treating or stabilizing HER2+ cancer, inhibiting HER2+ tumor metastasis, reducing the tumorigenicity of HER2+ tumor cells, and reducing the frequency of cancer stem cells or tumor initiation cells in HER2+ tumors. More specifically, the methods provided herein include administering a combination of peptide receptor radionuclides with immuno-oncological therapy. In some embodiments, the therapy may involve using a radiolabeled SSA peptide (somatostatin analog peptide) that has high affinity for somatostatin receptors (SSTRs) having radioisotopes such as Lu-177 in its overall structure. In the present invention, TRNT can be combined with standard therapy; trastuzumab and chemotherapy in a neoadjuvant setting, but can also be used with PD-1 and/or PD-L1/CDLA-4 or similar inhibitors. Tumor-targeted radionuclide therapy (TRNT) This method preferably involves administering a pharmaceutical composition that delivers cytotoxic radiation to cancer cells, particularly HER2+ cells, while minimizing toxicity to surrounding healthy tissue. This method also involves delivering a radioligand specifically designed to treat HER2+ cancer. This method may involve targeting HER2+ cancellation using a radiopharmaceutical, particularly an anti-integrin peptide mimetic, a chelating agent, and a radionuclide (such as [177] lutetium or [225] actinium). The anti-integrin peptide mimetic targets the HER2+ protein or characteristic cellular features, specifically determining the localization of the radiopharmaceutical, and the radionuclide carried by the composition is delivered to perform the treatment. The methods described herein also involve performing the diagnosis of cancer, particularly HER2+ cancer, as a therapeutic agent for non-invasive imaging by gamma-ray detection using positron emission tomography (PET) or single-photon emission computed tomography (SPECT), and/or for delivering cancer cell-killing radiation to targeted tumor cells. The composition is administered to the patient, and imaging is performed to determine the presence or prognosis of cancer, or for use in disease staging. This αvβ3 integrin antagonist peptidomimetic (or peptidomimetic drug/peptidomimetic agent) has high affinity for integrins on the surface of or within cancerous tumors, and precisely targets the HER2+ protein overexpressed in breast cancer. Administering a radiolabeled peptidomimetic agent targets HER2+ cancer in the patient or subject. TRNT and/or companion diagnostics for pretargeting are not available or approved by regulatory authorities for the treatment of any of the 10 types of breast cancer, including HER2-positive. TRNTs offer advantages over conventional cancer treatments, particularly the absence of side effects from chemotherapy or immunotherapy. Unlike external beam therapy, they are organ-specific and non-systemic, and have no dose limitations. Reduced renal excretion and/or hepatic degradation, prolonged circulation time and less accumulation in healthy non-target tissues, lead to site-avoiding drug delivery, accumulation at pathological sites, and site-specific drug delivery. Without the side effects of chemotherapy, TRNTs also result in high therapeutic index and accumulation at target sites. This compound enables drug delivery, drug release and efficacy monitoring, validation and optimization of combination therapies, and pre-screening of patients, thus enabling personalized medicine. Efficient targeting capability and rapid clearance offer high potential for targeted radionuclide therapy (TRNT). Pharmacokinetic and pharmacodynamic properties are consistent with the decay characteristics of short-lived α and β particles that emit radionuclides, providing a treatment option for solid tumors, metastatic and micrometastatic cancers, and residual disease. A preferred implementation of this method involves treating patients with human epidermal growth factor receptor 2-positive (hereinafter referred to as HER2+) or other cancers that overexpress integrin receptors with a pharmaceutical composition administered to the patient. This method involves administering to a patient a combination of an integrin antagonist peptide mimetic compound, which exhibits selective and high binding affinity to the α5β3 integrin receptor (h