Prostate cancer (CaP) is the most common non-skin cancer in men and third most common cause of cancer deaths in men. Black men experience a higher burden of incidence and mortality from CaP compared to White men. The Prostate-Specific Antigen (PSA) test, a commonly used biomarker for early diagnosis and management of CaP, cannot alone accurately predict the presence of CaP, its aggressiveness, or the risk of post-treatment recurrence. The widespread use of PSA testing in CaP screening is controversial partially because patients with benign enlargement of the prostate often have elevated levels of PSA and many men with diagnosed CaP have a normal PSA. Consequently, a search for more effective prostate tumor biomarkers is overdue. Our studies thus far show that concurrent measurements of the levels of serum cytokines such as IL-8, TNF-α, and sTNF-R1 (KAPS biomarker) provide a significant advantage as a CaP biomarker over PSA measurements alone in differentiating men with CaP from men without CaP. Our working hypothesis is that both Black and White men with CaP have altered circulating levels of KAPS biomarker compared to men without CaP. Further, the extent to which these levels are altered will vary according to CaP risk factors and can be used as a tool to improve the early detection of CaP and CaP treatment decision-making. We tested our hypothesis in a retrospective study of men with elevated PSA but a negative prostate biopsy, patients diagnosed with localized prostate cancer and patients with castration resistant CaP (CRPC). The predictive accuracy of the markers was described using receiver operating characteristic (ROC) curves.  In our analysis, AUC values greater than 0.8 were considered as useful in predicting CaP outcomes for individual patients. All the comparisons for KAPS biomarker were statistically significant at the p<0.05 level. The AUC for each of marker alone was statistically superior to PSA alone (p<0.01 for each pairwise comparison).  Each of the KAPS-marker combination AUCs was significantly better than PSA alone (p<0.01 for all), but not statistically different from each other.  Combining TNF-α with PSA resulted in a 3.0-fold decrease in the PSA-Alone False Positive Fraction (FPF), and a 3.7-fold decrease in the PSA- Alone False Negative Fraction (FNF).  The PSA+sTNFR1 combination had a 5.9-fold decrease in the FPF, and a 2.5-fold decrease in FNF. Ability of KAPS-biomarker was also effective at distinguishing between localized CaP and metastatic CaP patients. AUC results (with 95% confidence intervals) for additive combinations of these biomarkers will also be discussed. The best predictor of localized CaP vs. metastatic CaP was KAPS combined with PSA 0.999 (0.998 to 1.000). Due to the reported significant racial differences in the diagnoses of and mortality from CaP, future CaP biomarker studies should include a racially diverse sample of men, especially Black men.

Early observations showed a lack of growth control and terminal differentiation with a lack of gap junctional intercellular communication (GJIC). Subsequent observations showed that epigenetic tumor promoters and activated oncogenes, which block gap junction function, provide insights into the multi-stage, multi-mechanism carcinogenic process. With the isolation of embryonic induced pluri-potent stem cells and organ-specific adult stem cells, gap junctions were linked to early development. While tumors and tumor cell lines are a heterogeneous mixture of “cancer stem cells” and “cancer non-stem cells”, the cancer stem cells seem to be of two types, namely, they express (a) no connexin genes or (b) connexin genes, but do not have functional GJIC. These observations suggest that these “cancer stem cells” originate from normal adult stem cells or from the de-differentiation or re-programming of somatic differentiated cells. This “Concept Paper” provides a hypothesis that “cancer stem cells” either originate from (a) organ-specific adult stem cells before the expression of the connexin genes or (b) organ-specific adult stem cells that just express gap junction genes but that the connexin proteins are rendered dysfunctional by activated oncogenes. Therefore, cancer prevention and therapeutic strategies must account for these two different types of “cancer stem cell”.

Since early detection improves overall survival in lung cancer, identification of screening biomarkers for patients at risk represents an area of intense investigation. Tumor liberated protein (TLP) has been previously described as a tumor-associated antigen (complex) present in the sera from lung cancer patients. Here, we set out to identify the nature of TLP to develop this as a potential biomarker for lung cancer screening. Materials and Methods: Beginning from the peptide epitope RTNKEASI previously identified from TLP complex, we produced a rabbit anti-RTNKEASI serum and evaluated it in the lung cancer cell line A549 by means of immunoblot and peptide completion assay (PCA). The TLP sequence identification was conducted by mass spectrometry. The detected protein was, then, analyzed in patients with non small cell lung cancer (NSCLC), benign lung pathologies and healthy donors, by ELISA. Results: The anti-RTNKEASI antiserum detected and immunoprecipitated a 55kDa protein band in the lysate of A549 cells identified as aldehyde dehydrogenase isoform 1A1, revealing the molecular nature of at least one component of the previously described TLP complex. Next, we screened blood samples from a non-tumor cohort of 26 patients and 45 NSCLC patients with different disease stages for the presence of ALDH1A1 and global ALDH. This analysis indicated that serum positivity was highly restricted to patients with NSCLC (ALDH p<0.001; ALDH1A1 p=0.028). Interestingly, the global ALDH test resulted positive in more NSCLC samples compared to the ALDH1A1 test, suggesting that other ALDH isoforms might add to the sensitivity of the assay. Conclusion: Our data indicate that ALDH levels are elevated in the sera of NSCLC patients, even with early stage disease, and may thus be evaluated as part of a marker panel for non-invasive detection of NSCLC. 

TBA (Power point presentation)