Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer.

Pancreatic adenocarcinoma is one of the deadliest forms of cancer with no effective therapeutic options. A KRAS mutation can be found in up to 90% of all pancreatic tumors, making it a promising therapeutic target. The introduction of new KRAS inhibitors has been a milestone in the history of KRAS mutant tumors; however, therapeutic resistance limits their efficacy.

Identification of genetic fingerprint of type I interferon therapy in visceral metastases of melanoma.

Malignant melanoma is a difficult-to-treat skin cancer with increasing incidence worldwide. Although type-I interferon (IFN) is no longer part of guidelines, several melanoma patients are treated with type-I interferon (IFN) at some point of the disease, potentially affecting its genetic progression. We run genome-wide copy number variation (CNV) analysis on previously type-I IFN-treated (n = 17) and control (n = 11) visceral metastases of melanoma patients.

Different perspectives of prison guards and mental health workers in forensic care.

Objectives: This study investigates the differences in treatment perspectives of prison guards and mental health practitioners within a Psychiatric Prison Unit (PPU).

Methods: This qualitative study uses questionnaires and focus groups to explore the relationships between prison guards ( = 4) and mental health professionals ( = 6) working at the Psychiatric Prison Unit in Zwolle, the Netherlands. Two questionnaires (the Recovery Attitude Questionnaire and the Recovery Knowledge Inventory) were completed by the participants.

Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal.

[Farnesyltransferase inhibitors have antitumoral effects in mutant KRAS containing cancer cells in preclinical models].

In silico studies raised the possibility that farnesyltransferase inhibitors (FTIs) may have antitumoral effects on KRAS mutant cancer cells. Accordingly, we have tested FTIs (tipifarnib and lonafarnib) in G12C mutant human cancer cell lines in vitro and in vivo. We have discovered that the combination of the two drugs has a synergistic antitumoral effect.

Gluing GAP to RAS Mutants: A New Approach to an Old Problem in Cancer Drug Development.

Mutated genes may lead to cancer development in numerous tissues. While more than 600 cancer-causing genes are known today, some of the most widespread mutations are connected to the RAS gene; RAS mutations are found in approximately 25% of all human tumors. Specifically, KRAS mutations are involved in the three most lethal cancers in the U.

Comparison of standard mismatch repair deficiency and microsatellite instability tests in a large cancer series.

Background: The tumor-agnostic indication of immune checkpoint inhibitors to treat cancers with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) increased the demand for such tests beyond Lynch syndrome. International guideline recommendations accept immunohistochemistry (IHC) for dMMR or molecular techniques (PCR or NGS) for MSI status determinations considering the two tests are equal, although there are scattered reports contradicting to this presumption.

Materials And Methods: Here we have directly compared four protein MMR immunohistochemistry (IHC) to MSI Pentaplex PCR test in a large cancer patient cohort (n = 1306) of our diagnostic center where the two tests have been run parallel in 703 cases.

Farnesyl-transferase inhibitors show synergistic anticancer effects in combination with novel KRAS-G12C inhibitors.

Background: Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development.

KRASG12C mutant lung adenocarcinoma: unique biology, novel therapies and new challenges.

KRAS mutant lung cancer is the most prevalent molecular subclass of adenocarcinoma (LUAD), which is a heterogenous group depending on the mutation-type which affects not only the function of the oncogene but affects the biological behavior of the cancer as well. Furthermore, KRAS mutation affects radiation sensitivity but leads also to bevacizumab and bisphosphonate resistance as well. It was highly significant that allele specific irreversible inhibitors have been developed for the smoking associated G12C mutant KRAS (sotorasib and adagrasib).

[Potential role of type I interferon in the genetic progression of melanoma].

We have followed the genomic progression of cutaneous melanoma in visceral metastases using genome-wide copy number analysis. We have detected an increased chromosomal instability due to the loss of several DNA repair genes. Furthermore, we found co-amplifications of HGF and MET genes in metastases.

Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline.

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs.

[Molecular epidemiology of microsatellite instability/mismatch repair deficiency in our institute - methodical aspects].

Molecular epidemiology of mismatch repair deficiency (dMMR)/microsatellite instability (MSI) are different in various ethnic groups; accordingly, our aim was to test this in a large single-center Hungarian cancer patient cohort. We have found that dMMR/MSI incidence correlates well with TCGA data in case of colorectal, gastric and endometrial cancers. We have also observed that immunohistochemistry- based dMMR incidences are higher as compared to MSI.

The Driverless Triple-Wild-Type (BRAF, RAS, KIT) Cutaneous Melanoma: Whole Genome Sequencing Discoveries.

The genetic makeup of the triple-wild-type melanoma (BRAF, NRAS and NF1) has been known for some time, but those studies grouped together rare histopathological versions with common ones, as well as mucosal and even uveal ones. Here we used whole genome sequencing to genetically characterize the triple-wild-type melanoma (TWM), termed here as BRAF, RAS and KIT wild type (the most frequent oncogenic drivers of skin melanoma), using the most common histological forms and excluding rare ones. All these tumors except one were clearly induced by UV based on the mutational signature.

Metastatic Progression of Human Melanoma.

This Topical Collection, comprising 13 papers (10 original articles and 3 reviews), addresses various aspects of the field of melanoma progression: genomic and proteomic approaches, experimental studies, the questions of sentinel lymph node dissection, and metastasis formation of uveal and conjunctival melanomas is also discussed [...

Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry.

Cancer plasticity is now a recognized new hallmark of cancer which is due to disturbances of cell differentiation programs. It is manifested not only in various forms like the best-known epithelial-mesenchymal transition (EMT) but also in vasculogenic and megakaryocytic mimicries regulated by EMT-specific or less-specific transcription factors such as HIF1a or STAT1/2. Studies in the past decades provided ample data that cancer plasticity can be manifested also in the expression of a vast array of immune cell genes; best-known examples are PDL1/CD274, CD47, or IDO, and we termed it immunogenic mimicry (IGM).

Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas.

Objective: Administration of targeted therapies provides a promising treatment strategy for urachal adenocarcinoma (UrC) or primary bladder adenocarcinoma (PBAC); however, the selection of appropriate drugs remains difficult. Here, we aimed to establish a routine compatible methodological pipeline for the identification of the most important therapeutic targets and potentially effective drugs for UrC and PBAC.

Methods: Next-generation sequencing, using a 161 cancer driver gene panel, was performed on 41 UrC and 13 PBAC samples.

On-Target Side Effects of Targeted Therapeutics of Cancer.

The concept of precision medicine is based on the identification of hallmarks of cancer to exploit them as drug targets. The basic idea was that in this way the therapeutic modalities will be more effective and the side effects will be less. Since the majority of these novel modalities are not specific for a cancer-related biological process or a cancer-specific (mutant) target protein, it is not a surprise that we had to learn new type of side effects, because these therapeutics also affect physiological or pathological processes.

[Molecular pathology of skin melanoma].

Skin melanoma became one of the most frequent malignancies of the skin mainly due to the increased exposure to environmental UV irradiation. However, this did not lead to the increase of mortality, mainly due to the efficient early diagnostics as well as to the development of new therapies which were based on the identification of the mutation patterns and understanding of the immunobiology. Molecular markers are important to differentiate malignant tumors from precancerous ones but also routinely available to define prognosis.

Molecular Pathology of Skin Melanoma: Epidemiology, Differential Diagnostics, Prognosis and Therapy Prediction.

Similar to other malignancies, TCGA network efforts identified the detailed genomic picture of skin melanoma, laying down the basis of molecular classification. On the other hand, genome-wide association studies discovered the genetic background of the hereditary melanomas and the susceptibility genes. These genetic studies helped to fine-tune the differential diagnostics of malignant melanocytic lesions, using either FISH tests or the myPath gene expression signature.

Identification of a Tumor Cell Associated Type I IFN Resistance Gene Expression Signature of Human Melanoma, the Components of Which Have a Predictive Potential for Immunotherapy.

We developed a human melanoma model using the HT168-M1 cell line to induce IFN-α2 resistance in vitro (HT168-M1res), which was proven to be maintained in vivo in SCID mice. Comparing the mRNA profile of in vitro cultured HT168-M1res cells to its sensitive counterpart, we found 79 differentially expressed genes (DEGs). We found that only a 13-gene core of the DEGs was stable in vitro and only a 4-gene core was stable in vivo.

Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma.

Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays ( = 38 samples) to reveal organ specific alterations.