Methods and materials for assessing prostate cancer therapies
AssigneeThe Regents of the University of California
InventorsCharles Sawyer, Charlie Chen, Derek Welsbie
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Abstract
Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest (2-5 fold) increase in androgen receptor (AR) mRNA was the only expression change consistently associated with developing resistance to antiandrogen therapy. Increased levels of AR confer resistance to anti-androgens by amplifying signal output from low levels of residual ligand and altering the normal response to antagonists. This invention provides cell based assays for use in the examination of new therapeutic modalities and provides insight toward the design of novel antiandrogens.
Claims19
A method of examining the physiological effect of a compound on a mammalian prostate cancer cell wherein said prostate cancer cell expresses an exogenous wild type androgen receptor polynucleotide that encodes an androgen receptor polypeptide or an androgen receptor polypeptide variant, said cell further comprising an abnormal level of mRNA that encodes said androgen receptor polypeptide or, said androgen receptor polypeptide variant when compared to the level of mRNA that encodes said androgen receptor polypeptide or said androgen receptor polypeptide variant in a normal prostate cell, said method comprising:
- (a) determining that said abnormal level of mRNA in said prostate cancer cell is at least two fold higher than the level of mRNA in said normal prostate cell;
- (b) contacting a compound to be tested with said prostate cancer cell to provide a treated prostate cancer cell;
- and
- (c) examining one or more physiological characteristics of said treated prostate cancer cell.
A method of examining the physiological effect of a compound on a mammalian prostate cancer cell wherein said prostate cancer cell expresses an exogenous wild type androgen receptor polynucleotide that encodes an abnormal level of androgen receptor polypeptide or an abnormal level of androgen receptor polypeptide variant when compared to the level of androgen receptor polypeptide or androgen receptor polypeptide variant encoded by a normal prostate cell, said method comprising:
- (a) determining that said abnormal level of androgen receptor polypeptide or said abnormal level of androgen receptor polypeptide variant is at least two fold higher than the level of androgen receptor polypeptide or androgen receptor polypeptide variant in said normal prostate cell;
- (b) contacting a compound to be tested with said prostate cancer cell to provide a treated prostate cancer cell;
- and
- (c) examining one or more physiological characteristics of said treated prostate cancer cell.
A method of examining the physiological effect of a compound on a selected mammalian cancer cell wherein said cancer cell expresses an exogenous wild type polynucleotide that encodes a protein or polypeptide of interest, said cell further comprising an abnormal level of mRNA that encodes said protein or polypeptide of interest when compared to the level of mRNA that encodes said protein or polypeptide of interest in said normal selected cell, said method comprising:
- (a) determining that said abnormal level of mRNA in said selected cancer cell is at least two fold higher than the level of mRNA in said normal selected cell;
- (b) contacting a compound to be tested with said selected cancer cell to provide a treated cancer cell;
- and
- (c) examining one or more physiological characteristics of said treated cancer cell.
A method of examining the physiological effect of a compound on a-selected mammalian cancer cell wherein said selected cancer cell expresses an exogenous wild type polynucleotide that encodes an abnormal level of protein or polypeptide of interest when compared to the level of said protein or polypeptide of interest encoded by a normal selected cell, said method comprising:
- (a) determining that said abnormal level of said protein or polypeptide of interest is at least two fold higher than the level of said protein or polypeptide of interest in said normal selected cell;
- (b) contacting a compound to be tested with said selected cancer cell to provide a treated cancer cell;
- and
- (c) examining one or more physiological characteristics of said treated cancer cell.
A method of inhibiting the growth of hormone refractory prostate cancer cells wherein said cells comprise androgen receptors that exhibit biological function, said method comprising the step of decreasing the biological function of said androgen receptors.
A method for determining if a selected prostate cancer cell is hormone sensitive or has become hormone refractory, said method comprising the steps of:
- (a) determining the level of mRNA in said selected cell that encodes the androgen receptor polypeptide or androgen receptor polypeptide variant;
- (b) determining the level of mRNA in a hormone sensitive selected prostate cancer cell;
- (c) comparing the level of mRNA determined in step (a) to the level of mRNA determined in step (b);
- and
- (d) determining that the selected prostate cancer cell is hormone sensitive or has become hormone refractory if the level of mRNA determined in step (a) is at least two fold higher than the level of mRNA determined in step (b).
A method for determining if a selected prostate cancer cell is hormone sensitive or has become hormone refractory, said method comprising the steps of:
- (a) determining the level of androgen receptor polypeptide or the level of androgen receptor polypeptide variant in said selected cell;
- (b) determining the level of androgen receptor polypeptide or the level of androgen receptor polypeptide variant in a hormone sensitive selected prostate cancer cell;
- (c) comparing the level of androgen-receptor polypeptide or the level of androgen receptor polypeptide variant determined in step (a) to the level of androgen receptor polypeptide or the level of androgen receptor polypeptide variant determined in step (b) and
- (d) determining that the selected prostate cancer cell is hormone sensitive or has become hormone refractory if the level of androgen receptor polypeptide or the level of androgen receptor polypeptide variant determined in step (a) is at least two fold higher than the level of androgen receptor polypeptide or the level of androgen receptor polypeptide variant determined in step (b).
Dependencies are inferred from the claim text.