Insulin-like growth factor system and cancer

Details Insulin-like growth factor system and cancer Insulin-like growth factor system and cancer

2000-01-18

2002-09-10

Caputa, Anthony C. (Department: 1642)

Chemistry: analytical and immunological testing

Cancer

C436S813000, C435S004000, C435S007100, C435S007230

Reexamination Certificate

active

06448086

ABSTRACT:

BACKGROUND
1. Field of the Invention
This invention relates to the measurement of the IGF-axis component levels and tumor marker levels for use in assessing cancer risk and/or progression and/or distinguishing between cancer and other non-malignant disorders. The invention is exemplified with prostate cancer (CaP) and benign prostatic hyperplasia (BHP), the tumor marker prostate specific antigen (PSA), and the insulin-like growth factors (IGF) and their binding proteins (IGFBP). Specifically, IGF-I, intact IGFBP-3, fragment IGFBP-3, total IGFBP-3, free PSA and total PSA were assayed and certain permutations of these measurements were found to present improved diagnostic indicators. The method is predicted to have general applicability to other IGF-system related cancers.
2. Description of the Prior Art
The insulin-like growth factor (IGF) family of high affinity IGF binding proteins (IGFBP-1-6) (1-4) has recently evolved to a superfamily status in order to accommodate a related group of newly discovered low affinity IGFBPs called the IGFBP related proteins (5). The conventional view of IGFBPs as the sole regulators of IGF bioavailability and bioactivity has also evolved to include the IGF-independent properties of IGFBPs (6, 7). IGFBPs, particularly IGFBP-3, have been recently identified as potent apoptotic agents (8-12), presumably mediating the effects of cellular growth suppressing mechanisms (8, 11, 12). The emerging new concept appears to similarly broaden the pathophysiological roles of the IGF peptides to include their potential involvement in regulation of the IGFBPs' bioactivity (8). In this ever-expanding maze of reciprocal molecular interactions, post-translational modification by selective proteolysis is rapidly gaining acceptance as the key modulator of the IGF/IGFBP system and a major determinant of their effects on cellular growth and metabolism (13, 14).
Insulin-like growth factors (IGF-I and -II) are mitogenic and anti-apoptotic agents produced primarily by the liver and locally by a wide variety of tissues. IGFs circulate mostly complexed with IGFBP-3, which in association with the acid-labile subunit (ALS) forms an approximately 150 kD ternary protein complex (1-4). Under normal conditions, nearly all of the circulating IGFs remain ternary complexed (75-80%), and smaller proportions (20-25%) are associated with the low molecular weight IGFBPs (IGFBP-1, IGFBP-2, IGFBP4, IGFBP-5, and IGFBP-6) or exist in the free form (1-4).
Dysregulation and/or over-expression of the IGF system have been long implicated in the etiology of both benign and malignant proliferative disorders (3, 4, 15-19). Malignant cells of various origins have been shown to express various components of the IGF system (3, 4, 11-13, 18-22), and increased IGF-I levels, as seen in acromegaly, have been found in association with benign prostatic hyperplasia (BPH) (23, 24) and colonic tumors (25, 26). High levels of circulating IGF-I has been more recently identified as risk factors for the development of prostate, breast, and lung cancers (27-30), while over-expression of both IGF-I and IGF-II has been linked to colorectal cancers (31). In prostate, both benign and malignant cells have been found to express IGFs, IGFBPs and their respective receptors (18, 23). IGF-I has been shown to promote prostate cell growth, while prostate specific antigen (PSA) has been identified as an IGFBP-3 protease, presumably capable of augmenting tissue access to the IGF peptides (18, 23, 32).
In men over 50 years of age, cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH) are among the most commonly diagnosed malignant and benign proliferative disorders, respectively (33). However, serum levels of PSA, the most reliable predictor of CaP available to date, is also increased in BPH, resulting in a diagnostic “gray-zone” in the PSA range of ~4-10 &mgr;g/L (34). In addition, PSA levels of less than 4 &mgr;g/L does not necessarily indicate disease-free status because significant numbers of men with organ-confined CaP reportedly express normal PSA levels (35). These significant limitations of PSA testing invariably result in a diagnostic dilemma, allowing for loss opportunity for early cancer detection, or unnecessary surgical approaches to a readily treatable benign disorder. Although the ratio of free/total PSA levels in serum is significantly reduced in CaP and its determination is now used to heighten the diagnostic accuracy of PSA testing (36, 37), there is still a great need to further improve our ability to discriminate between BPH and prostate cancer (35).
SUMMARY OF THE INVENTION
Abbreviations and Definitions
ACT—alpha-1-antichymotrypsin.
ALS—Acid Labile Subunit. A protein found in the 150 kD ternary complex wherein most of the circulating IGF-I is found. ALS is sensitive to inactivation by acid, urea and certain detergents.
Body fluid—Any biological fluid, including but not limited to the following: serum, plasma, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, mammary fluid, whole blood, urine, spinal fluid, saliva, sputum, tears, perspiration, mucus, tissue culture medium, tissue extracts and cellular extracts. Preferably, the body fluid is blood, plasma, serum or seminal fluid.
BHP—benign prostatic hyperplasia.
CaP—cancer of the prostate.
DHT—Dihydrotestosterone.
GH—Growth hormone.
GHBP—GH binding protein.
IGF—Insulin-like Growth Factor.
IGF-axis components—Those components that modulate the IGF/GH cascades including GH, GHBP, GH receptor, IGF I and II, IGF receptors, IGF proteases, IGFBP-1 through -6 and the IGFBP related proteins IGFBP-rP-1-9, IGFBP proteases, ALS, IGF and GH receptor antagonists, and the like. Altered levels of IGF axis components are known to be associated with a variety of malignant diseases, including breast, ovarian, endometrial, colorectal and prostate cancer, as discussed herein, and also with papillary thyroid cancer, Wilms tumor and possibly other CNS tumors, choroid plexus papilloma, meningiomas, hepatocellular carcinoma, rhabdomyosarcoma, gastric carcinomas, liver cancer, and colon cancer, leukemias, pituitary adenomas and tumors, and lung cancer.
IGFBP—Any IGF binding protein, including IGFBP-1 to 6 and the IGFBP related proteins IGFBP-rP-1 to 9.
IGFBP-3—The major circulating IGF binding protein. Intact IGFBP-3 refers to that portion of the total IGFBP-3 which is undegraded (and exists mainly in complexed form). Fragment IGFBP-3 refers to the fragmented forms of IGFBP-3. With the assay described herein, amino terminal fragments of IGFBP-3 that lack the carboxyl terminal amino acids are detected as fragment IGFBP-3. Total IGFBP-3 refers to complexed, uncomplexed, intact and fragmented IGFBP-3. The various forms of IGFBP-3 are referred to collectively as “IGFBP-3 variants.”
Indicator ratio—As used herein a ratio of the measured levels of IGF axis components with or without kallikrein-like components, such as PSA, which is useful to distinguish between benign and cancerous conditions or useful in monitoring the progression of a cancerous disease. The specification teaches how to evaluate various permutations of measurements of IGF axis components and tumor markers and test for clinically significant associations. For example, an indicator ratio of IGF-I/free PSA means the concentration of IGF-I divided by the concentration of free PSA.
Kallikrein—A group of serine proteases with homology to PSA, including at least K1, K2, and preprokallikreins. “Kallikrein-like proteins” includes the kallikreins and various forms of PSA.
PSA—Prostate specific antigen. Free PSA is the fraction of PSA that is not complexed with other proteins, such as ACT. Total PSA is free PSA and complexed PSA.
Ratio—Any ratio referred to herein expressly refers to and includes the inverse ratio. Thus if the ratio of IGF-I/free PSA is informative about a particular disease state, of course the ratio of free PSA/IGF-I will be equally informative.
SHBG—Sex hormone binding globulin.
T—Testosterone.
Tumor Marker—As used herein, the term includes any marker associa

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