Anti-SSBP2 monoclonal antibody Made to order

Purpose: Prostate cancer is a major cause of cancer death among men and the development of new biomarkers is important to augment current detection approaches. Experimental Design: We identified hypermethylation of the ssDNA-binding protein 2 (SSBP2) promoter as a potential DNA marker for human prostate cancer based on previous bioinformatics results and pharmacologic unmasking microarray. We then did quantitative methylation-specific PCR in primary prostate cancer tissues to confirm hypermethylation of the SSBP2 promoter, and analyzed its correlation with clinicopathologic data. We further examined SSBP2 expression in primary prostate cancer and studied its role in cell growth. Results: Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer. Reactivation of SSBP2 expression by the demethylating agent 5-aza-2'-deoxycytidine in prostate cancer cell lines confirmed epigenetic inactivation as one major mechanism of SSBP2 regulation. Moreover, forced expression of SSBP2 inhibited prostate cancer cell proliferation in the colony formation assay and caused cell cycle arrest. Conclusion: SSBP2 inhibits prostate cancer cell proliferation and seems to represent a novel prostate cancer - specific DNA marker, especially in high stages of human prostate cancer.

Newtherapies for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) patients are urgently needed. The genetic landscape of Ph-like ALL is characterized by a diverse array of kinase-activating alterations (including rearrangements, sequence mutations, and copy number alterations), suggesting that patients with Ph-like ALL are candidates for targeted therapy, similar to BCR-ABL1 ALL. We sought to investigate the functional role and targetability of the spectrum of kinase-activating alterations identified in Ph-like ALL. We demonstrate cytokine-independent growth and activation of JAK-STAT signaling pathways in Ba/F3 cells by all alterations tested. The development of murine Arf(-/-) pre-B ALL expressing RCSD1-ABL2 or SSBP2-CSF1Rwas accelerated with the presence of IK6, a dominant negative isoform of Ikaros common in Ph-like ALL, providing evidence that these fusions are leukemogenic. In vitro screening using a panel of tyrosine kinase inhibitors against 14 different kinase alterations identified the ABL1-inhibitor, dasatinib, as a potent inhibitor of ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB), whereas the JAK1/JAK2 inhibitor ruxolitinib, was most effective against JAK-STAT-activating alterations (JAK1, JAK2, JAK3, IL7R, IL2RB), but not TYK2. Evaluation of dasatinib or ruxolitinib against patient-derived xenograft models demonstrated superior antileukemic efficacy when combined with dexamethasone compared with either agent alone. These data provide the foundation for rationally designed clinical trials that assess the efficacy of targeted therapy in patients with Ph-like ALL.