Chemistry: analytical and immunological testing – Cancer
Reexamination Certificate
1999-01-21
2002-06-25
Caputa, Anthony C. (Department: 1642)
Chemistry: analytical and immunological testing
Cancer
C436S063000, C435S004000
Reexamination Certificate
active
06410335
ABSTRACT:
BACKGROUND
1. Field of the Invention
The present invention relates to a method for assessing the risk of developing prostate cancer in an individual. Increased risk for prostate cancer is correlated with high insulin-like growth factor status (IGF status). Specifically, the method involves measurement of IGF-I and/or insulin-like growth factor binding protein-3 (IGFBP-3) in a specimen. High levels of IGF and/or low levels of IGFBP correlate with increased risk of developing prostate cancer.
In an alternative embodiment, the method involves determining the IGF/PSA status of an individual wherein the determination of IGF status is combined with a measurement of prostate specific antigen (PSA) levels. The IGF/PSA status provides an improved method of assessing the prognosis of existing prostate cancer.
Furthermore, novel treatment modalities are suggested by the discovery of the link between IGF-axis component levels and prostate cancer that involve modulating IGF-axis component levels.
2. Description of the Prior Art
Prostate adenocarcinoma accounts for the majority of malignancies in males over the age of 65. Yearly screening for prostate cancer is recommended after the age of 45. There has been considerable effort toward identifying suitable prostate cancer markers to assist in predicting, diagnosing and monitoring this disease.
Prostate specific antigen (PSA) is recognized as the most sensitive marker of prostatic adenocarcinoma (M. K. Brawer
Cancer
71(suppl):899-905 (1993); J. E.
Oesterling J. Urol.
145:907-23 (1991)). PSA is also recognized as a proven screening vehicle (P. H. Gann, et al.
Amer. Med. Assoc.
273:289-94 (1995); W. J. Catalona, et al.
J. Urol.
151:1283-90 (1994)). It has been the most sensitive front line test for identifying prostate gland-contained, and hence presumably curable, cancer. PSA has also been useful in detecting clinically significant tumors, as opposed to latent, indolent micro-carcinomas. Screening for PSA is even superior to the common office practice of digital rectal examination (DRE). For example, Labrie et al. (
Clin. Invest. Med.
16:425-39 (1993)) showed that 97% of cancers detected at annual follow-up by DRE plus PSA testing were PSA-positive. Thus, only a minimal benefit accrues from including DRE in the medical evaluation.
Investigators have searched for other markers or indicators of prostate cancer, but to date PSA has been the most useful marker. No one has heretofor studied the association of IGF-axis components with prostate cancer.
Insulin-like growth factors (IGF-I and IGF-II) belong to family of peptides that mediate a broad spectrum of growth hormone-dependent as well as independent mitogenic and metabolic actions. Unlike most peptide hormones, IGFs in circulation and other physiological fluids are associated with a group of high affinity binding proteins (IGFBPs) that specifically bind and modulate their bioactivity at the cellular level. Under normal conditions about 95-98% or the IGF-I in human plasma is bound to IGFBPs. Six structurally homologous IGFBPs with distinct molecular size, hormonal control, and tissue expression and functions, have been identified (J. I. Jones, et al.
Endocrinol. Reviews
16:3-34, (1995)). Most serum IGF-I circulates in a relatively stable ternary complex consisting of IGFBP-3 and a unique leucine-rich, acid-labile subunit (ALS). Less than one percent of IGF-I is estimated to exist in a “free” or unbound form.
The rate of cell proliferation is positively correlated with risk of transformation of certain epithelial cell types. S. M. Cohen and L. B. Ellwein.
Science
249:1007 (1990); S. M. Cohen and L. B. Ellwein.
Cancer Research
51:6493 (1991). IGFs have mitogenic and anti-apoptotic influences on normal and transformed prostate epithelial cells. A. Y. Hsing, K. Kadomatsu, M. J. Bonharn, D. Danielpour.
Cancer Research
56:5146 (1996); Z. Culig, A. Hobisch, M. V. Cronauer, C. Radmayr, J. Trapman, A. Hittmair, G. Hartsch, B. Klocker.
Cancer Research
54:5474 (1994); P. Cohen, D. M. Peehl, R. G. Rosenfeld.
Hormone and Metabolic Research
26:81 (1994); M. Iwamura, P. M. Stuss, J. B. Casamento, A. T. Cockett.
Prostate
22:243 (1993); P. Cohen, D. M. Peehl, G. Lamson, R. G. Rosenfeld.
J. Clinical Endocrinology
&
Metabolism
73:401 (1991); R. Rajah, D. Valentino, and P. Cohen.
J. Biol. Chem.
272:12181 (1997). Most circulating IGF-I originates in the liver, but IGF bioactivity in tissues is related not only to levels of circulating IGFs and IGFBPs, but also to local production of IGFs, IGFBPs, and IGFBP proteases. J. J. Jones and D. R. Clemmons.
Endocrine Reviews
16:3 (1995). Person-to-person variability in levels of circulating IGF-I and IGFBP-3 (the major circulating IGFBP (J. J. Jones and D. R. Clemnmons.
Endocrine Reviews
16:3 (1995) is considerable (A. Juul, P. Bang, N. T. Hertel, K. Main, P. Dalgaard, K. Jorgensen, J. Muller, K. Hall, N. E. Skakkebaek.
J. Clinical Endocrinology
&
Metabolism
78:744 (1994); A. Juul, P. Dalgaard, W. F. Blum, P. Bang, K. Hall, K. F. Michaelsen, J. Muller, N. E. Skakkeback.
J. Clinical Endocrinology
&
Metabolism
80:2534 (1995) and heterogeneity in serum IGF-I level appears to reflect heterogeneity in tissue IGF bioactivity. Acromegaly and growth hormone deficiency are examples where there are clear changes in tissues that are correlated with serum IGF-I level, implying a relationship between serum IGF-I level and tissue IGF-I bioactivity. Also, factors that decrease circulating IGF-I level also affect expression of genes in target organs for IGF-I action in a manner that decreases IGF bioactivity. For example, antiestrogens lower IGF-I level (M. Pollak, J. Constantino, C. Polyochronakos, S. Blauer, H. Guyda, C. Redrnond, B. Fisher, R. Margolese.
JNCI
82:1693 (1990), but also increase IGFBP expression (H. Huynh, X. Yang, B. Deroo, M. Pollak.
Cell Growth and Differentiation
7:1501 (1996); H. Huynh, X. Yang, M. Pollak.
J Biol Chem
271:1016 (1996) and decrease IGF-I receptor expression (H. Huynh, T. Nickerson, M. Pollak.
Clinical Cancer Research
2:2037 (1996) in cells that are targets for IGF-I action. No one has heretofore shown that markers relating to IGF-axis components can also be used as a risk marker for prostate cancer.
SUMMARY OF THE INVENTION
Abbreviations and Definitions
AAG—3—alpha-androstanediol glucuronide.
ALS—Acid Labile Subunit. A protein found in the 150 KDa ternary complex wherein most of the circulating IGF is found. ALS is sensitive to inactivation by acid.
Binary complex—A two part complex of IGFBP and ALS or IGFBP and IGF.
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.
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, IGF receptor, IGF proteases, IGFBP 1 through 6 and other IGFBPs, ALS, IGF proteases, IGF and GH receptor antagonists, and the like.
IGF—axis component modulating agent—also: IGF status modulating agents. Includes any agent whose intended effect is to influence the GH or IGF cascades. Agents include GH, GHBP, IGF, IGFBP, ALS, IGFBP complex, GH receptors, IGF receptors, antibodies or modulators of any of the preceding, receptor antagonists for GH or IGF, or any drug that acts to modulate the IGF status of an individual including somatostatin, somatostatin analogues, GH antagonists, IGF antagonist, IGFBP stimulator, and the like.
IGFBP—Any IGF binding protein, including IGFBP-1 to 6 and the heretofore unsequenced IGFBPs. Preferably, the IGFBP is IGFBP-3 in the context of the assay described herein.
IGFBP-3—The major circulating IGF binding protein.
IGFBP complex—This term is defined herein to incl
Giovannucci Edward
Pollak Michael N.
Stampfer Meir J.
Caputa Anthony C.
Haynes and Boone LLP
Holleran Anne L.
The Brigham and Woman's Hospital, Inc.
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