A tumormarker-kutatás rövid története. A PSA, mint legismertebb urológiai tumormarker felfedezésének története

There are a number of tumour markers available today enabling the early detection of malignancies thus saving the lives of many thousands of people worldwide. By definition, tumour markers are substances in tissues, blood, bone marrow or other body fluids that appear in cancer patients’ samples or are present at significantly elevated levels compared to normal conditions. The first marker of malignant disease in modern medicine was identified in 1846 by the English physician-chemist Henry Bence-Jones. Yet, at that time, of course, he was not aware that the protein (named as Bence-Jones) he discovered, was a pathogenic indicator of multiple myeloma. The classic era of tumour markers started in the 1960s with the discovery of two leading oncofetal antigens, alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA). AFP was published in 1944 by Swedish scientist Kai O. Pedersen, while the discovery of CEA is associated with two Canadian physicians, Phil Gold and Samuel O. Freedman. One of the most widely known tumour markers indicating prostate cancer is the prostate-specific antigen or PSA. The discovery of PSA as a clinically useful marker of prostate cancer and its translation into clinical practice can be attributed to Ming C. Wang, who described the molecule in 1979. The US Food and Drug Administration (FDA) approved PSA in 1986 as a molecule for monitoring the disease, and in 1994 it licenced the measuring of PSA levels as a screening test, thus facilitating the early detection of prostate cancer and enabling more effective treatment.

MODL-28. IMMUNE PRIMING WITH INTERFERON-Γ COMBINED WITH EPIGENETIC MODULATION IN PEDIATRIC BRAIN TUMORS

Systemic interferon-γ (IFNγ) has been shown to induce major histocompatibility complex class I (MHC-I) and T cell infiltration in solid tumors in adult patients, demonstrating a potential strategy to abrogate tumor-intrinsic mechanisms of immune escape. Pediatric brain tumors (PBT) may be particularly sensitive to this approach but have a paucity of immunogenic tumor antigens for presentation on MHC-I. Decitabine and other DNA methyltransferase (DNMT) inhibitors promote expression of oncofetal antigens and endogenous immune responses through epigenetic alterations. We tested the convergence of these immune priming mechanisms using a novel combination of IFNγ and decitabine across a spectrum of PBT. Primary human cell lines (Med-411FH, PBT-05FH, GBM-511FH, CCHMC-GBM-1, CCHMC-GBM-4, ATRT-310FH) and murine transgenic models were treated with IFNγ alone or in combination with decitabine and evaluated expression of cell surface MHC-I and PD-L1, interferon response genes (ISGs), and oncofetal antigens. PBT showed exquisite sensitivity to IFNγ, increasing expression of MHC-1/PD-L1 along with ISGs (TAP1, MX1, IRF1). Decitabine enhanced IFNγ-induced gene expression of oncofetal antigens NY-ESO-1 and MAGE-A1. In a medulloblastoma flank tumor model, MHC-I was increased by 40-fold following intraperitoneal IFNγ treatment (p=0.01), with a 3-fold increase in PD-L1 (p=0.005) compared to untreated controls. Effect on CD8+ T cell killing and validation in humanized models is ongoing. Immune priming of PBT with IFNγ is feasible and results in more substantial MHC-I upregulation compared to hypomethylating agents alone. These results provide a strong rationale for priming prior to checkpoint inhibition as a compelling therapeutic strategy in immunologically-quiescent PBT.

Opportunities for Antibody Discovery Using Human Pluripotent Stem Cells: Conservation of Oncofetal Targets

Pluripotent stem cells (PSCs) comprise both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The application of pluripotent stem cells is divided into four main areas, namely: (i) regenerative therapy, (ii) the study and understanding of developmental biology, (iii) drug screening and toxicology and (iv) disease modeling. In this review, we describe a new opportunity for PSCs, the discovery of new biomarkers and generating antibodies against these biomarkers. PSCs are good sources of immunogen for raising monoclonal antibodies (mAbs) because of the conservation of oncofetal antigens between PSCs and cancer cells. Hence mAbs generated using PSCs can potentially be applied in two different fields. First, these mAbs can be used in regenerative cell therapy to characterize the PSCs. In addition, the mAbs can be used to separate or eliminate contaminating or residual undifferentiated PSCs from the differentiated cell product. This step is critical as undifferentiated PSCs can form teratomas in vivo. The mAbs generated against PSCs can also be used in the field of oncology. Here, novel targets can be identified and the mAbs developed as targeted therapy to kill the cancer cells. Conversely, as new and novel oncofetal biomarkers are discovered on PSCs, cancer mAbs that are already approved by the FDA can be repurposed for regenerative medicine, thus expediting the route to the clinics.

Genetic Differences Between Humans and Great Apes –Implications for the Evolution of Humans

At the level of individual protein sequences, humans are 97–100% identical to the great apes, our closest evolutionary relatives. The evolution of humans (and of human intelligence) from a common ancestor with the chimpanzee and bonobo involved many steps, influenced by interactions amongst factors of genetic, developmental, ecological, microbial, climatic, behavioral, cultural and social origin. The genetic factors can be approached by direct comparisons of human and great ape genomes, genes and gene products, and by elucidating biochemical and biological consequences of any differences found. We have discovered multiple genetic and biochemical differences between humans and great apes, particularly with respect to a family of cell surface molecules called sialic acids, as well as in the metabolism of thyroid hormones. The hormone differences have potential consequences for human brain development. The differences in sialic acid biology have multiple implications for the human condition, ranging from susceptibility or resistance to microbial pathogens, effects on endogenous receptors in the immune system, and potential effects on placental signaling, expression of oncofetal antigens in cancers, consequences of dietary intake of animal foods, and development of the mammalian brain.