Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving viable micro-organism
Reexamination Certificate
1998-11-10
2002-07-09
Gitomer, Ralph (Department: 1623)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving viable micro-organism
C435S030000
Reexamination Certificate
active
06416967
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
A system is provided for in vitro tracking of cancerous tissue over the course of the malignancy. The system provides a method for identifying the malignancy and for determining a patient's prognosis. Further, the system provides for assessing a malignancy's invasiveness, aggressiveness, growth rate, production of extracellular markers, possible side effects and for determining the efficacy on the malignancy of a given therapeutic regimen. The system also allows for generation of a therapeutic index, which serves as an indicator of a given therapy's effectiveness against the malignancy as compared to its undesirable side effects, such as lethality to a patient's normal cells.
INTRODUCTION
Tracking a malignancy in a patient according to prior art methods is an inaccurate process which involves identification of the malignancy through techniques including biopsy and subsequent histological, biochemical, and immunochemical techniques and regularly monitoring the malignancy's progression by invasive (i.e., biopsy) or noninvasive (i.e., x-ray, nuclear imaging, Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET)) methods. These methods are often expensive, inconvenient, painful and usually involve hospital visits and safety risks. It is, therefore, desirable to reduce a patient's exposure to such methods. Furthermore, identification of a malignancy as a known variety of malignancy is often helpful in determining a suitable therapeutic approach and expected prognosis. However, even individually identifiable malignancies differ from patient-to-patient in their growth characteristics and in their responsiveness to treatment.
Determination of the growth rate, invasiveness and aggressiveness of a given malignancy is critical to prognosis and to the choice of therapies. A patient with a poor prognosis might be given a therapeutic regimen which might be more effective than another regimen but more risky to the patient. A patient with a better prognosis might be given a therapeutic regimen which is less aggressive and less risky to the patient, but which might not be as effective as often as a more dangerous therapy. Similarly, if a malignancy produces factors or creates conditions which cause a dangerous side effect, such as a thrombogenesis, the patient can be treated, preferably prophylactically, for the condition.
Current methodologies for determining growth rate, invasiveness, aggressiveness or which track the progression of a malignancy include biopsy and short-term culture, which can include drawing of blood or other bodily fluids, or semi- or non-invasive techniques such as x-ray and nuclear imaging. At any given time, a patient could be subject to multiple procedures, depending upon when the information is needed by the physician. Each procedure requires the presence of the patient and usually creates risk or pain. These procedures also can increase the stress level of the patient, which often is an exacerbating factor in cancer and associated prognoses. It is therefore, desirable to reduce the frequency of such procedures.
Identification of an effective therapeutic regimen is critically important to a patient. Often, once the malignancy is identified, a therapy is chosen based upon prior research on that type of malignancy and is not tailored to the sensitivities of the malignancy of a given patient. Often secondary therapies are needed because a first choice was ineffective. Valuable treatment time can be lost and a patient's life can be threatened.
All active agents including chemotherapeutic active agents are subjected to rigorous testing as to efficacy and safety prior to approval for medical use in the United States. Methods of assessing efficacy have included elaborate investigations of large populations in double blind studies as to a given treatment method and/or active agent, with concomitant statistical interpretation of the resulting data, but these conclusions are inevitably generalized as to patient populations taken as a whole. In many pharmaceutical disciplines and particularly in the area of chemotherapy, however, the results of individual patient therapy may not comport with generalized data—to the detriment of the individual patient. The need has been long recognized for a method of assessing the therapeutic potential of active agents, including but not limited to chemotherapeutic agents, for their efficacy as to a given individual patient, prior to the treatment of that patient. This need also applies to assessing the therapeutic potential as to radiation therapies, combined radiation/drug therapies and cellular immunotherapies.
Prior art assays already exist which expose malignant tissue of various types to a plurality of active agents, for the purpose of assessing the best choice for therapeutic administration. For example, in Kruczynski, A., et al., “Evidence of a direct relationship between the increase in the in vitro passage number of human non-small-cell-lung cancer primocultures and their chemosensitivity,”
Anticancer Research
, vol. 13, no. 2, pp. 507-513 (1993), chemosensitivity of non-small-cell-lung cancers was investigated in vivo grafts, in vitro primocultures and in commercially available long-term cancer cell lines. The increase in chemosensitivity was documented and correlated with morphological changes in the cells in question. Sometimes animal model malignant cells and/or established cell cultures are tested with prospective therapy agents, see for example Arnold, J. T., “Evaluation of chemopreventive agents in different mechanistic classes using a rat tracheal epithelial cell culture transformation assay,”
Cancer Res
., vol. 55, no. 3, pp. 537-543 (1995).
In vitro prior art techniques present the further shortcoming that assayed cells do not necessarily express the cellular markers they would express in vivo. This is regrettable because the determination of expression of certain secreted or cellular markers, secreted factors or tumor antigens or lack thereof can be useful for both identification and therapeutic purposes. For instance, members of the fibrinolytic system such as urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitors type 1 (PAI-1) are up-regulated in malignant brain tumors. See, e.g., Jasti S. Rao, et al., “The Fibrinolytic System in Human Brain Tumors: Association with Pathophysiological Conditions of Malignant Brain Tumors,”
Advances in Neuro
-
Oncology II
, Kornblith P L, Walker M D (eds) Futura (1997). Other secreted factors such as &agr;-fetoprotein, carcinoembryonic antigen and transforming growth factors &agr; and &bgr; have been found to be indicative of various cancers and/or cancer progression (see also, Singhal et al., “Elevated Plasma Osteopontin in Metastatic Breast Cancer Associated with Increased Tumor Burden and Decreased Survival,”
Clinical Cancer Research
, vol. 3, 605-611, (April 1997); Kohno et al., “Comparative Studies of CAM 123-6 and Carcinoembryonic Antigen for the Serological Detection of Pulmonary Adenocarcinoma,”
Cancer Detection and Prevention
, 21 (2): 124-128 (1997)). These examples are but a few of the many factors that may be used to identify diseased cells.
Cellular markers also include metastatic markers, indicative of metastatic potential, i.e., invasiveness and aggressiveness, which is relevant to the progression of a given malignancy and to a patient's prognosis. First, markers indicating the invasiveness of a given malignancy indicate the ability of the malignancy to infiltrate and to destroy adjacent tissue. As an example, for epithelial malignancies, invasiveness markers are indicative of the ability of the malignancy to infiltrate beneath the epithelial basement membrane. Invasiveness markers can include the presence of proteolytic enzymes or angiogenic factors. A second category of metastatic marker indicates growth conditions of the malignancy. For instance, a malignancy could require for instance a prostate-specific factor for growth. Invasiven
Gitomer Ralph
Precision Therapeutics, Inc.
Webb Ziesenheim & Logsdon Orkin & Hanson, P.C.
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