Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-03-19
2001-03-13
Schwartzman, Robert A. (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023100, C536S024500, C435S375000
Reexamination Certificate
active
06200754
ABSTRACT:
BACKGROUND
This invention is concerned with the field of treatment of proliferative disorders, including malignant and nonmalignant proliferative diseases.
The following information is provided to assist the understanding of the reader, none of that information is admitted to be prior art to the present invention.
The treatment of cancer is one of the most heavily investigated areas in biomedical research today. Although many anticancer drugs have been and continue to be discovered, there remains the immense problem of developing drugs that will be specifically toxic to cancer cells without killing normal cells and causing toxic, often permanent, damage to vital organs or even death. One common measure of the clinical usefulness of any anticancer drugs is its therapeutic index: the ratio of the median lethal dose (LD
50
) to the median effective dose (ED
50
) of the drug. With some cancer therapeutics this ratio is in the range of 2-4, indicating a high risk of toxic side effects to the patient. Indeed, most anticancer drugs are associated with a high incidence of adverse drug events. The poor therapeutic index of most anticancer drugs not only limit the clinical efficacy of these drugs for the treatment of cancer, but limits their usefulness for treating many non-malignant, proliferative disorders.
A strategy for the development of anticancer agents having a high therapeutic index is described in Housman, International Application PCT/US/94 08473 and Housman, INHIBITORS OF ALTERNATIVE ALLELES OF GENES ENCODING PROTEINS VITAL FOR CELL VIABILITY OR CELL GROWTH AS A BASIS FOR CANCER THERAPEUTIC AGENTS, U.S. Pat. No. 5,702,890, issued Dec. 30, 1997, which are hereby incorporated by reference in their entireties. As further described below, the method involves the identification of genes essential to cell growth or viability which are present in two or more allelic forms in normal somatic cells of a cancer patient and which undergo loss of heterozygosity in a cancer. Treatment of a cancer in an individual who is heterozygous with an allele specific inhibitor targeted to the single allele of an essential gene which is present in a cancer will inhibit the growth of the cancer cells. In contrast, the alternative allele present in non-cancerous cells (which have not undergone loss of heterozygosity) is able to express active product which supplies the essential gene function, so that the normal cells can survive and/or grow.
Cancer cells from an individual almost invariably undergo a loss of genetic material (DNA) when compared to normal cells. Frequently, this deletion of genetic material includes the loss of one of the two alleles of genes for which the normal somatic cells of the same individual are heterozygous, meaning that there are differences in the sequence of the gene on each of the parental chromosomes. The loss of one allele in the cancer cells is referred to as “loss of heterozygosity” (LOH). Recognizing that almost all, if not all, varieties of cancer undergo LOH, and that regions of DNA loss are often quite extensive, the genetic content of deleted regions in cancer cells was evaluated and it was found that genes essential for cell viability or cell growth are frequently deleted, reducing the cancer cell to only one copy. Further investigation demonstrated that the loss of genetic material from cancer cells sometimes results in the selective loss of one of two alleles of a certain essential gene at a particular locus or loci on a particular chromosome.
Based on this analysis, a therapeutic strategy for the treatment of cancer was developed, which will produce agents characterized by a high therapeutic index. The strategy includes: (1) identification of genes that are essential for cell survival or growth; (2) identification of common alternative alleles of these genes; (3) identification of the absence of one of these alleles in cancer cells due to LOH and (4) development of specific inhibitors of the single remaining allele of the essential gene retained by the cancer cell, but not the alternative allele.
SUMMARY OF THE INVENTION
While the patent identified above describes a beneficial approach to cancer therapy using allele specific inhibitors of essential genes, it was found in the present invention that a new class of genes can also provide advantageous treatment methods for cancer or other proliferative disorders involving loss of heterozygosity, based on genetic differences in one or more of those genes between normal somatic cells and cells of the proliferative disorder. While the following discussion is principally presented in the context of cancer treatment, those skilled in the art will undertand that non-malignant proliferative disorders can instead be involved, as described in Housman et al., TARGET GENES FOR ALLELE-SPECIFIC DRUGS, attorney docket number 232/116, filed the same day as the present application, which is hereby incorporated by reference in its entirety including drawings.
It was recognized that environmental factors can cause certain genes to be essential that are not essential under other conditions (including usual in vivo and culture conditions). For example, certain genes involved in intermediary metabolism are not essential if the cell or organism is supplemented with high concentrations of a particular nutrient or chemical entity, but if that nutrient or chemical entity is absent or present at low levels, the gene product is essential. In another example, the administration of a drug that inhibits one or more functions within the cell can cause other functions to be essential that are not essential in the absence of the drug. In another example, subjecting a cell to harsh physical agents, such as radiation, can cause certain genes to be essential that are not essential under normal conditions. Such genes are essential under certain conditions associated with the therapy of cancer. The demonstration that such genes are present in the population in more than one allelic form and are subjected to loss of heterozygosity in cancer or noncancer proliferative disorders makes such genes targets for allele specific drugs for the treatment of such disorders.
It was found that such genes, similar to generally essential genes, are frequently deleted due to LOH in cells of proliferative disorders such as cancers.
Thus, the present invention is directed to the use of genes which are referred to as conditionally essential genes as targets or as indicators of an appropriate antiproliferative treatment. Such conditionally essential genes are those which are necessary or beneficial to the growth, proliferation, or survival of a cell under particular environmental conditions, but not under normal in vivo conditions. Treatment methods involving such genes can provide enhanced sensitivity of cancer cells to a variety of different anti-proliferative treatments, including radiation and administration of various compounds. Unless otherwise indicated, the term “essential” includes both strictly essential and beneficial to cell growth or survival.
A gene is said to be “conditionally essential” if it is essential for cell survival or proliferation in a specific environmental condition caused by the presence or absence of specific environmental constituents, pharmaceutical agents, including small molecules or biologicals, or physical factors such as radiation, or if the gene enhances the growth or survival of the cell under such conditions by at least 2-fold, preferably by at least 4-fold, and more preferably by at least 6-fold, 10-fold or even more.
Cancer cells, as well as cells from a number of different non-malignant proliferative disorders, from an individual almost invariably undergo a loss of genetic material (DNA) when compared to normal cells. Frequently, this deletion of genetic material includes the loss of one of the two alleles of genes for which the normal somatic cells of the same individual are heterozygous, meaning that there are differences in the sequence of the gene on each of the parental chromosomes. The loss of one allele in the cancer cells
Housman David E.
Ledley Fred D.
Stanton, Jr. Vincent P.
Epps Janet L.
Schwartzman Robert A.
Variagenics Inc.
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