JOACHIM YAHALOM, MD
Radiology at York Ave, New York, NY

2002015, Oct 24, 2002

Dec 4, 2001

10/006957

Shoshana Paglin - New York NY, US
Joachim Yahalom - New York NY, US
Timothy Hollister - Chicago IL, US
Thomas Delohery - Oakland NJ, US

A61K031/7048, A61N005/00

514/028000, 600/001000

The present invention relates to methods and compositions for inhibiting cell survival and/or promoting cell death following exposure to cytotoxic agents and stress such as radiation or chemotherapy exposure through inhibition of V-H-ATPase. In particular, the formation and/or acidification of acidic vesicular organelles (AVOs) may be prevented or decreased by inhibiting the activity of vacuolar proton ATPase (“V-H-ATPase”). The methods and compositions of the invention are based on the observation that (i) following irradiation surviving cancer cells accumulate AVOs and that their acidification is mediated by V-H-ATPase; (ii) surviving colonies of cells contain higher levels of AVOs; and (iii) inhibition of V-H-ATPase decreases the clonogenic survival of cells irradiated or exposed to chemotherapeutic agents. These observations led to the conclusion that V-H-ATPase activity and AVO function serve to protect cells from radiation and chemotherapy damage. In addition, agents such as bFGF, TNF-, PMA, rapamycin and tamoxifen were shown to be inducers of acidic organelle formation. Therefore signal transduction pathways mediated by these agents provide targets for drug screening assays designed to identify inhibitors of V-H-ATPase activity and AVO formation/acidification. The present invention may be used to treat cancer subjects through sensitization of neoplastic cells to the toxic effects of radiation and chemotherapy.

2003016, Aug 28, 2003

Sep 20, 2002

10/251210

Shlomit Gilad - Gedera, IL
Joachim Yahalom - New York NY, US

C12Q001/68

435/006000

There is provided a method of testing a subject to determine if the subject has a predisposition for developing a cancer, a cancer of epithelial origin such as lung cancer, colon cancer, prostate cancer, ovarian cancer, bladder cancer, and cancer of the pancreas, and also a lymphoproliferative malignancy such as Hodgkin's disease and non-Hodgkin's lymphoma. This method includes the steps of detecting a mutation in the open reading frame of the ATM gene (SEQ.ID.NO:1) in a cDNA sample or a genomic DNA sample from the subject, which mutation is selected from the group consisting of the mutations set forth in Table 3 and Table 4; or, detecting a mutation in the mRNA corresponding to the open reading frame of the ATM gene (SEQ.ID.NO:1) in a mRNA sample from the subject, which mutation is selected from the group consisting of RNA complementary to the mutations set forth in Table 3 and Table 4, wherein the presence of such a mutation indicates that the subject has a predisposition for developing cancer. Also provided is an isolated cDNA molecule having a nucleotide sequence which differs from the sequence set forth in SEQ.ID.NO:1 by a mutation selected from the group consisting of mutations 378 T→A, 3383 A→G, 1636 C→G, 2614 C→T, 6437 G→C, 2932 T→C, 2289 T→A, 6096 A→T, 6176 C→T, 6919 C→T, 2442 C→A, 3925 G→A, 6067 G→A, 2119 T→C, 1810 C→T, and 4388 T→G. An oligonucleotide probe which is capable of detecting a mutation in the open reading frame of the ATM gene is also provided. Additionally, kits for detection and prediction of cancer are provided.