Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-01-27
2001-10-02
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001490, C424S001650, C424S130100
Reexamination Certificate
active
06296833
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of medical diagnostics and therapeutics. It is specifically directed to methods for detecting and treating cancer based upon the expression of the calcium-sensing receptor (CaR) in transformed tissue.
BACKGROUND OF THE INVENTION
An extracellular calcium-sensing receptor (CaR) has been cloned from both bovine and human parathyroids, as well as from human kidney tissue and rat brain (Pollak, et al.,
Cell
75:1297-1303 (1993); Aida, et al.,
Biochem. Biophys. Res. Commun
. 214:524-529 (1995); Ruat, et al.,
Proc. Nat'l Acad. Sci. USA
92:3161-3165 (1995)). This receptor appears to play a key role in regulating extracellular calcium homeostasis (Pollak, et al.,
Nature Genet
. 8:303-307 (1994); Pollak, et al.,
J. Clin. Invest
. 93:1108-1112 (1994)).
Previous studies have suggested that calcium may be important in processes leading to tumor formation and spread. For example, it is known that cancerous breast and brain tissue tends to form microcalcifications (Galkin, et al.
Radiology
124:245-249 (1977)) and calcium has been shown to stimulate cellular division and differentiation. Defining the relationship between calcium and tumor cell biology may lead to new clinical approaches to treating cancer patients. The present invention is based upon the discovery that CaR, a primary regulator of calcium, is expressed at abnormal levels in human tumors. This has led to the development of new diagnostic and therapeutic methods.
SUMMARY OF THE INVENTION
The present invention is directed to a method for treating cancer in a human patient by administering a ligand that binds with specificity to CaR. Specific conditions that may be treated in this manner include breast cancer, prostate cancer, multiple myeloma, brain tumors, Leydig cell tumors, colon cancer, renal cell carcinoma, cervical cancer, ovarian cancer, vulvar cancer, skin cancer, esophageal cancer, lung cancer and cancers of the head or neck. For the purposes of the present invention, a ligand “binds with specificity” if it has at least a hundred-fold greater affinity for CaR than for any other protein. It is expected that some cancers will respond to calcium agonists whereas others will respond to calcium antagonists. The preferred calcium agonists are those agents described in PCT/US93/01642 and U.S. Pat. No. 5,688,938 (particularly the compound designated as NPS S-568). Other examples of calcium agonists that may be used include protamine and neomycin. An example of a calcium antagonist that may be administered to patients is suramin. However, other small molecular weight antagonists may be developed that will offer advantages over suramin and be preferred.
The calcium ligand should be administered at a dosage and for a duration sufficient to produce an improvement in one or more of the symptoms associated with the cancer being treated. Examples of such symptomatic improvement include a stabilization or reduction in tumor size or growth, a reduction in metastases, a normalization of calcium metabolism as reflected in parameters such as blood or tissue calcium concentrations, rate of bone resorption, etc. It has been discovered that CaR-specific ligands may be used to inhibit the production of parathyroid hormone related peptide (PTH-RP). Thus, antagonists may be given to a patient with cancer at a dosage sufficient to reduce plasma levels of PTH-RP and thereby reduce symptoms associated with aberrant calcium metabolism, particularly excessive bone resorption, or hypercalcemia.
The present invention is also directed to a method for detecting neoplastically transformed cells in a human patient by quantitating the number of CaR receptors present in test tissue, e.g. tissue obtained at biopsy, and comparing the results to those obtained from tissue known to be normal. The presence of transformed cells is indicated by a statistically significant increase or decrease in receptor number. One way to determine receptor number is by carrying out a binding assay using a detectably labeled ligand that binds with specificity to CaR. In a preferred embodiment, the ligand used in this method is a CaR-specific antibody. Biopsy tissue for use in the method includes tissue from the breast, prostate, brain, lung, cervix, ovary, colon or tissue comprised of Leydig cells. In the case of tissue from the colon, the presence of transformed cells is indicated by a lower number of CaR receptors compared to the number of CaR receptors in normal colon tissue.
In another aspect, the present invention is directed to a method for determining whether an abnormal growth, typically a tumor-like mass, in a human patient is cancerous. This is accomplished by administering a compound that binds with specificity to the calcium-sensing receptor and that is labeled with an agent that allows the compound to be detected using in vivo imaging techniques such as X-rays, sonograms, CAT scans, or magnetic resonance imaging. The extent to which the detectably labeled compound of step a) becomes localized in the abnormal growth is then determined and compared with the amount in tissue known to be noncancerous. If the amount of labeled compound in the abnormal growth is present at a statistically higher or lower level than the amount found in the nontransformed tissue, this is an indication that the abnormal growth is cancerous. It is expected that this method will be especially useful in determining whether a lump in a woman's breast is a cyst or a cancerous growth. The method may also be used to examine abnormal growths from the colon, lung, or brain.
In other work, it has been discovered that, when the calcium-sensing receptor is activated, cells become more resistant to apoptosis. This suggests two ways in which agents that interact with CaR may be used to augment the action of chemotherapeutic agents. In cases where a patient is treated with a chemotherapeutic agent that acts by inducing apoptosis in cancer cells, the method may be improved by the coadministration of a CaR antagonist. The antagonist should be administered at a dosage sufficient to sensitize the cancer cells, i.e. to induce a statistically significant higher percentage of the cells to undergo apoptosis in response to a fixed concentration of chemotherapeutic agent. Any method may be used to determine whether a given dosage of antagonist has caused apoptotic activity in cells to change. For example, cells may be stained and examined microscopically to determine the percentage with an apoptotic morphology (nuclear and cytoplasmic condensation, nuclear fragmentation, membrane blebbing, and apoptotic body formation). By performing such an assay both before and after the administration of CaR antagonist, one can determine if a statistically significant change has occurred.
In cases where a patient is treated with a chemotherapeutic agent that acts by some means other than inducing apoptosis in cancer cells but which induces apoptosis in normal cells as a side effect, the method may be improved by the coadministration of a CaR agonist. The agonist should be administered at a dosage effective to make cells more resistant to apoptosis. In this manner, the therapeutic efficacy of a treatment may be maintained while its undesirable side effects are decreased. In addition the invention includes the compositions that are used in the methods. Thus, it includes both compositions comprising a cancer chemotherapeutic agent and a CaR antagonist and compositions comprising a cancer chemotherapeutic agent and a CaR agonist.
The present invention encompasses not only a method for augmenting cancer chemotherapy as discussed above, but also, more generally, a method of altering the sensitivity of the cells of a mammal to apoptosis by administering an effective dose of a ligand that binds with specificity to the CaR receptor. Thus, CaR agonists and antagonists may be used in the treatment of diseases characterized by abnormal apoptotic activity, including autoimmune diseases and AIDS. The agents should be given at a dosage effective to cause an improvement
Brown Edward M.
Soybel David I.
Jones Dameron L.
Pillsbury & Winthrop LLP
Sanzo Michael A.
The Brigham and Women's Hospital Inc.
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