Assays for Cancer Patient Monitoring Based on Levels of Analyte Components of the Plasminogen Activator System in Body Fluid Samples

Abstract

The present invention describes clinically and medically important methods of examining, screening over time, and monitoring the outcome of a cancer patient who is undergoing treatment or therapy for his or her disease. More specifically, the invention provides a method of monitoring the progression of disease, or the effectiveness of cancer treatment, in a cancer patient by measuring the levels of one or more analytes of the plasminogen activator (uPA) system, namely, uPA, PAI-1 and the complex of uPA:PAI-1, in a sample taken from the cancer patient, preferably, before treatment, at the start of treatment, and at various time intervals during treatment. As a result of performing the method, an increase or elevation in the levels of one or more of the PA system analytes in the cancer patient compared with the levels one or more of the respective PA system analytes in normal control individuals serves as an indicator of cancer advancement or progression and / or a lack of treatment effectiveness for the patient.

Description

FIELD OF THE INVENTION[0001]The present invention relates to assays for monitoring or assessing the progress of cancer patients during a course of disease or disease treatment or therapy by determining levels of one or more cancer analytes, i.e., components of the plasminogen activator (PA) system, compared to the levels of one or more of these PA system components in normal control individuals. According to the methods described herein, the determination of increases in the levels of one or more of urokinase plasminogen activator (uPA), PA inhibitor-1 (PAI-1), or a complex of uPA and PAI-1 (the uPA:PAI-1 complex), compared with the levels of these respective analytes in normal controls is indicative of poor patient and / or treatment outcome relative to disease status.BACKGROUND OF THE INVENTION[0002]The plasminogen activator (PA) system involves the serine proteases plasmin and urokinase plasminogen activator (uPA); the serpins α2-antiplasmin, plasminogen activator inhibitor type-1 ...

AI Technical Summary

Benefits of technology

[0043]An advantage of the present invention is the ability to monitor, or screen over time, those patients who can benefit from one, or several, of the available cancer therapies, and preferably, to monitor patients receiving a particular type of therapy, or a combination therapy, over time to determine how the patient is faring from the treatment(s), if a change, alteration, or cessation of treatment is warranted; if the patient's disease has been reduced, ameliorated, or lessened; or if the patient's disease state or stage has progressed, or become metastatic or invasive. The cancer treatments embraced herein also include surgeries to remove or reduce in size a tumor, or tumor burden, in a patient. Accordingly, the methods of the invention are useful to monitor patient progress and disease status post-surgery.

[0044]The identification of the correct patients for a cancer therapy according to this invention can provide an increase in the efficacy of the treatment and can avoid subjecting a patient to unwanted and life-threatening side effects of the therapy. By the same token, the ability to monitor a patient undergoing a course of therapy using the methods of the present invention can determine whether a patient is adequately responding to therapy over time, to determine if dosage or amount or mode of delivery should be altered or adjusted, and to ascertain if a patient is improving during therapy, or is regressing or is entering a more severe or advanced stage of disease, including invasion or metastasis, as discussed further herein.

[0045]A method of monitoring according to this invention reflects the serial, or sequential, testing or analysis of a cancer patient by testing or analyzing the patient's body fluid sample over a period of time, such as during the course of treatment or therapy, or during the course of the patient's disease. For instance, in serial testing, the same patient provides a body fluid sample, e.g., serum or plasma, or has sample taken, for the purpose of observing, checking, or examining the levels of uPA, PAI-1, or the complex of uPA:PAI-1 in the patient by measuring the levels of one or more of these analytes during the course of treatment, and / or during the course of the disease, according to the methods of the invention.

[0046]Similarly, a patient can be screened over time to assess the levels of one or more of the PA system analytes in a body fluid sample for the purposes of determining the status of his or her disease and / or the efficacy, reaction, and response to cancer or neoplastic disease treatments or therapies that he or she is undergoing. It will be appreciated that one or more pretreatment sample(s) is / are optimally taken from a patient prior to a course of treatment or therapy, or at the start of the treatment or therapy, to assist in the analysis and evaluation of patient progress and / or response at one or more later points in time during the period that the patient is receiving treatment and undergoing clinical and medical evaluation.

[0047]In monitoring a patient's uPA, PAI-1 or uPA:PAI-1 complex levels over a period of time, which may be days, weeks, months, and in some cases, years, or various intervals thereof, the patient's body fluid sample, e.g., a serum or plasma sample, is collected at intervals, as determined by the practitioner, such as a physician or clinician, to determine the levels of one or more of the PA system analytes in the cancer patient compared to the respective levels of one or more of these analytes in normal individuals over the course or treatment or disease. For example, patient samples can be taken and monitored every month, every two months, or combinations of one, two, or three month intervals according to the invention. Quarterly, or more frequent monitoring of patient samples, is advisable.

[0048]The levels of the one or more PA system analytes found in the patient are compared with the respective levels of the one or more of these PA system analytes in normal individuals, and with the patient's own PA system analyte levels, for example, obtained from prior testing periods, to determine treatment or disease progress or outcome. Accordingly, use of the patient's own PA system analyte levels monitored over time can provide, for comparison purposes, the patient's own values as an internal personal control for long-term monitoring of uPA, PAI-1, and / or uPA:PAI-1 complex levels. As described herein, following a course of treatment or disease, the determination of an increase in one or more of the PA system component levels in the cancer patient over time compared to the respective levels of one or more of these analytes in normal individuals reflects the ability to determine the severity or stage of a patient's cancer, or the progress, or lack thereof, in the course or outcome of a patient's cancer therapy or treatment.

Problems solved by technology

Because the PA system components are intricately involved in the process of cancer and cancer spread in a variety of cancer types, which afflict both genders, it is a problem in the art to be able to accurately and sensitively screen over time to determine and monitor those individuals who are likely to respond, and / or who are responding to, (or not responding to), or benefiting from (or not benefiting from), anti-cancer therapy(ies), or combination therapies, particularly, molecularly targeted therapies to the plasminogen activation system.

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