Compositions of trail and DNA damaging drugs and uses thereof

Details Compositions of trail and DNA damaging drugs and uses thereof Compositions of trail and DNA damaging drugs and uses thereof

1999-09-30

2002-09-03

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

Reexamination Certificate

active

06444640

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compositions useful in treating patients afflicted with diseases involving rapid cellular turnover, such as cancer, and methods of treatment which utilize these compositions. More particularly, it relates to treatment of cancers such as glioblastomas.
BACKGROUND AND PRIOR ART
Malignant glioma is the most common primary brain tumor. Notwithstanding a number of intensive, multimodality treatments including surgical resection, irradiation and chemotherapy, gliomas are considered to be incurable. The 5 year survival rate of patients with glioblastoma multiforme, the most malignant form of glioma, is less than 10%. See, e.g., Dean, et al., J. Neuroncol 16: 243-272 (1993). Genetic analyses have defined a number of alterations which accumulate during the malignant progression of gliomas, including alterations in the TP53, CDKN2A, RB1, PTEN, EGFR, and MDM2 genes. See Nagane, et al., Curr. Opin. Oncol 9: 215-222 (1997), incorporated by reference on this issue. It also now seems to be the case that glioblastomas can be divided into two distinct genetic subsets, where p53 inactivation and amplification of EGFR are mutually exclusive genetic lesions. See Louis, et al., Trends Genet. 11: 412-415 (1995); Reifenberger, et al., J. Neuorpathol. Exp. Neural 55: 822-831 (1996); Watanabe, et al., Brain Pathol. 6: 217-223 (1996). About 40% of glioblastomas exhibit p53 mutations, and progress from lower grade lesions. Other glioblastomas with wild type p53 occur de novo, mostly in older patients, exhibit rapid clinical course, and are frequently associated with EGFR alterations. See Louis et al., supra; Reifenberger, et al., supra. There is some evidence that these, latter de novo type of glioblastoma may be more resistant to chemotherapy than other types (Mason, et al., J. Clin. Oncol 15: 3423-3426 (1997), and studies have shown that malignant gliomas in younger patients respond significantly better to chemotherapy than those in older patients. See Grant, et al., Neurol 45: 929-933 (1995).
In vitro studies have shown that astrocytes from p53 knockout mice are more sensitive to 1,3 bis (2-chloroethyl)-1-nitrosourea(“BCNU” hereafter) than are wild type astrocytes. See Nutt, et al., Cancer Res 56: 2748-2751 (1996). Further, overexpression of mutant EGFR, which is common in de novo glioblastoma has been demonstrated to confer drug resistance in human glioblastoma cells which exhibit wild type p53. See Nagane, et al., Proc. Natl. Acad. Sci. USA 95: 5724-5729 (1998). Hence, clinically more aggressive, “de novo” glioblastoma remains a major obstacle for successful glioma therapy.
It is known that the p53 tumor suppressor protein is a major regulator of cell cycle arrest, DNA repair, and apoptosis that is induced upon DNA damage, and other forms of genotoxic stress. See Roley, et al., Important Adv. Onco 1996: 37-56 (1996). Since most de novo type glioblastomas retain wild type p53, one possible approach to treatment might be to activate and to utilize the apoptosis related functions of p53.
There are multiple pathways involved in p53 mediated apoptosis. Further, a family of so-called “death receptors”, or “DRs” which contain cytoplasmic death domains have been found to be transcriptionally upregulated, in p53 dependent manner, by DNA damage, in some human cancer cells. See Muller, et al., J. Clin. Invest. 99: 403-413 (1997); Sherkh, et al., Cancer Res. 58: 1593-1598 (1998); Wu, et al., Nature Genet. 17: 141-143 (1997).
One such receptor, “DR
5
,” also named “killer/TRAIL-R2” specifically binds to tumor necrosis factor related apoptosis inducing ligand, or “TRAIL.” Information on “TRAIL” can be found in, e.g., U.S. Pat. No. 5,763,223, incorporated by reference. DRS, via binding to TRAIL, mediates TRAIL induced apoptosis via activation of effector caspases. See Wu, et al., supra; Wiley, et al., Immunity 3: 673-682 (1995); Pitti, et al., J. Biol. Chem 271: 12687-12690 (1996); Pan, et al., Science 277: 815-818 (1997); Sheridan, etal., Science 217: 818-821 (1997); Walczak, et al., EMBO J 16: 5386-5397 (1997). TRAIL also binds to another death receptor, “DR4,” (Pan, et al., Science 276: 111-113 (1997)), which is another receptor that mediates apoptosis, as well as to two additional receptors, i.e., DcR1(TRID/TRAIL-R3), and DcR2 (TRUNDD/TRAIL-R4), both of which lack death domains. See Pan, et al., Science 277: 815-818 (1997); Sheridan, et al., Science 277: 818-821 (1997); Degli-Esposti, et al., J. Exp. Med. 186: 1165-1170 (1997); Degli-Esposti, et al., Immunity 7: 813-820 (1997); Marsters, et al., Curr. Biol 7: 1003-1006 (1997); Pan, et al., Febs Lett 424: 41-45 (1998).
In view of this information, it was of interest to determine if TRAIL, in combination with DNA damaging drugs, could be used to alleviate cancers, such as glioblastoma. How this is accomplished is the subject of the invention which is set forth in the disclosure which follows.


REFERENCES:
patent: 5763223 (1998-06-01), Wiley et al.

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