Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-03-12
2003-07-22
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000
Reexamination Certificate
active
06596712
ABSTRACT:
BACKGROUND OF THE INVENTION
I. Information Relating to Previous Squalamine Applications
This invention relates to various methods for using squalamine. Squalamine, having the structure illustrated in
FIG. 1
, is an aminosterol which has been isolated from the liver of the dogfish shark,
Squalus acanthias
. This aminosterol is the subject of U.S. Pat. No. 5,192,756 to Zasloff, et al., which patent is entirely incorporated herein by reference. Methods for synthesizing squalamine have been devised, such as the methods described in WO 94/19366 (published Sep. 1, 1994). This PCT publication is entirely incorporated herein by reference. This PCT application also relates to U.S. patent Appln. Ser. No. 08/023,347 (filed Feb. 26, 1993), which application also is entirely incorporated herein by reference. Additional methods for synthesizing squalamine also are described in U.S. patent Appln. Ser. No. 08/985,876 filed Dec. 5, 1997, which application also is entirely incorporated herein by reference.
U.S. Pat. Nos. 5,733,899 and 5,721,226 describe the use of squalamine as an antiangiogenic agent. These U.S. patents are entirely incorporated herein by reference. Additional uses of squalamine (e.g., as a sodium/proton exchanger (isoform 3), or NHE3, inhibiting agent and as an agent for inhibiting the growth of endothelial cells) and squalamine synthesis techniques are disclosed in U.S. Pat. No. 5,792,635. This U.S. patent is also entirely incorporated herein by reference.
II. Information Relating to this Invention
About 50,000 new cases of CNS (central nervous system) tumors are diagnosed each year. Of these, about 35,000 are metastatic tumors (e.g., lung, breast, melanomas) and about 15,000 are primary tumors (mostly astrocytomas). Astrocytomas, along with other malignant gliomas (i.e., cancers of the brain), are the third leading cause of death from cancer in persons between the ages of 15 and 34.
Treatment options for a patient with a CNS tumor are very limited. Currently, surgery is the treatment of choice. Surgery provides a definite diagnosis, relieves the mass bulkiness of the tumor, and extends survival of the patient. The only post-surgery adjuvant treatment which is known to work on CNS tumors is radiation, and it can prolong survival. Radiation treatment, however, has many undesirable side effects. It can damage the normal tissue of the patient, including the brain tissue. Radiation also can cause the patient to be sick (e.g., nausea) and/or to temporarily lose their hair.
The other common post-surgery adjuvant cancer treatment, chemotherapy, is relatively ineffective against CNS tumors. Specifically, chemotherapy against CNS tumors with nitrosoureas is not curative. Many other cancer treating agents have been studied and tested, but generally they have a minimal effect on extending survival.
In view of these limited treatment options, the current prognosis for persons with CNS tumors is not good. The median survival term for patients with malignant astrocytomas having surgery and no adjuvant treatment is about 14 weeks. Radiation therapy after surgery extends the median to about 36 weeks. The current two year survival rate for all forms of treatment is less than 10%.
To maximize survival, it is critical to begin treatment in the early stages of CNS tumor development. Typically, the extent of tumor angiogenesis (i.e., blood vessel formation) correlates with survival in the patient. CNS tumors are among the most angiogenic of all human tumors. When the tumor is small, however, it is in an “avascular” phase, and its growth is restricted by a diffusion mechanism (i.e., the cells receive their nutrition, etc. by diffusion into the cell). In this phase, the tumor is viable, but not growing, and it is unable to spread. Over time, however, angiogenesis begins and the tumor converts to a “vascular” phase. In this phase, perfusion replaces diffusion as the growth mechanism, and tumor growth is exponential (i.e., the tumor has its own blood vessels to provide nutrients, etc.). Mitotic cells cluster around new blood vessels and metastases occur in the vascular phase (i.e., the tumor can spread to other areas in the body). Therefore, by treating the tumor early (before it reaches the vascular phase), one can hope to inhibit metastatic spread as well as control the primary tumor.
Other types of cancer also are difficult to combat by known cancer treatments. Lung cancer kills more Americans annually than the next four most frequently diagnosed neoplasms combined. Estimates for 1994 indicate more than 170,000 new cases of lung cancer and approximately 150,000 deaths (Boring et al.; CA Cancer J. Clin. 1994, 44: 7-26). Approximately 80% of primary lung tumors are of the non-small cell variety, which includes squamous cell and large cell carcinomas, as well as adenocarcinomas.
Single-modality therapy is considered appropriate for most cases of early and late stage non-small cell lung cancer (NSCLC). Early stage tumors are potentially curable with surgery, chemotherapy, or radiotherapy, and late stage patients usually receive chemotherapy or best supportive care. Intermediate stage or locally advanced NSCLC, which comprises 25% to 30% of all cases of NSCLC, is more typically treated with multimodality therapy. This is a stage of tumor development when angiogenesis is a very important factor. New blood vessels are needed to support further tumor growth and for the development of metastases. Therefore, this stage is amenable to treatment with antiangiogenic agents to prevent the development of new blood vessels. The efficacy of this therapy can be further improved by the combination of the antiangiogenic therapy with cytotoxic chemotherapy or radiation therapy to eliminate existing tumor.
Breast cancer also presents treatment difficulties using known agents. The incidence of breast cancer in the United States has been rising at a rate of about 2%/year since 1980, and the American Cancer Society estimated that 182,000 cases of invasive breast cancer were diagnosed in 1995. Breast cancer is usually treated with surgery, radiotherapy, chemotherapy, hormone therapy, or combinations of the various methods. Like other solid tumors, breast cancer requires the development of new blood vessels to support its growth beyond a certain size, and at that stage in its development, it will be amenable to treatment with antiangiogenic agents.
A major reason for the failure of cancer chemotherapy in breast cancer is the development of resistance to the cytotoxic drugs. Combination therapy using drugs with different mechanisms of action is an accepted method of treatment which prevents development of resistance by the treated tumor. Antiangiogenic agents are particularly useful in combination therapy because they are not likely to cause resistance development since they do not act on the tumor, but on normal host tissue.
Prostate cancer is another cancer for which new therapies are needed. Despite the prevalence of prostate cancer as the most frequently diagnosed malignancy among American men, mechanisms of prostate carcinogenesis are poorly understood. The multiplicity of factors involved in the development, proliferation, and dissemination of human prostate cancer, as well as their relationships and interaction with one another, magnify the difficulty of treatment.
Both prostate tumor cell growth and metastasis require adequate metabolic support as well as vascular access and thus rely on angiogeneis. The prostate cancer cell-extracellular matrix (ECM)/stromal relationship is also significant to the growth and spread of human prostate cancer. Of the numerous growth factors present in the ECM, b-FGF (basic fibroblast growth factor, also known as FGF-2) and VEGF (vascular endothelial growth factor) stand out as having been implicated in both inducing a malignant phenotype and in promoting and maintaining angiogenic processes. Ultimately, the outcome of a patient with prostate cancer largely depends upon the tumor's capacity for unhindered growth, local invasion, and the establishment of distant metastasis. Thus
Sokoloff Mitchell H.
Williams Jon
Zasloff Michael
Genaera Corporation
Goldberg Jerome D.
Morgan & Lewis & Bockius, LLP
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