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Polo-like kinase 1 (Plk1) is a critical protein involved in regulation of mitosis, and aberrant expression of this kinase is found in various cancer types.  Inhibition of Plk1 is currently being pursued in pre-clinical drug development for novel anti-cancer therapeutics.  Plk1 contains an allosteric domain, known as the polo-box domain (PBD), that is responsible for localizing the kinase domain to mitotic structures through protein-protein interactions.  

Researchers at the National Cancer Institute (NCI) have developed orthotopic allograft models for pancreatic cancer that utilize low passage primary pancreatic adenocarcinoma cells or tumor fragments implanted into the cancer-free pancreata of recipient syngeneic immunocompetent mice. Tumor development in these models is more synchronized, latency is substantially shortened, and tumors develop only in one location, as pre-determined by the choice of a site for cells/tumor fragment implantation.

Adoptive cell therapy (ACT) using genetically engineered T-cell receptors (TCRs) is a promising cancer treatment. These TCRs target genetic mutations unique to patients and play an important role in tumor regression. However, mutation-reactive T-cells and their TCRs can be difficult to identify and isolate from patients. Therefore, we need more efficient methods of isolating mutation-reactive T-cells for use with ACT. 

The development of an effective HIV vaccine has been an ongoing area of research. High variability in HIV-1 virus strains, however,  represents a major challenge.  Ideally, an effective candidate vaccine would provide protection against the majority of clades of HIV.  Two major hurdles to overcome are immunodominance and sequence diversity. Researchers at the National Cancer Institute (NCI) have developed a vaccine that overcomes these major hurdles by utilizing a strategy that identifies conserved regions of the virus and exploits them for use in a targeted therapy.

Although multidimensional diffusion/relaxation NMR experiments are widely used in materials sciences and engineering applications, preclinical and clinical MRI applications of these techniques were not feasible. Moreover, higher-field MRI scanners posed another obstacle to translation of this NMR method. Their specific absorption rate (SAR) limits the use of multi-echo or CPMG pulse trains, so that the large amounts of data required by these methods cannot be collected in vivo due to exceedingly long scan times.

Steroid hormones have been implicated to play a fundamental role in the pathogenesis of prostate cancer. Polymorphisms in the genes that code for enzymes, or hormones involved in androgen regulatory pathway, reportedly influence risk for developing prostate cancer. Since many membrane transporters are modulators of steroid hormones absorption and tissue distribution, genetic polymorphisms in genes encoding these transporters may account for the risk of prostate cancer and the predicting of survival.

Inflammatory processes associated with the over-production of tumor necrosis-alpha (TNF-alpha), a potent activator of the immune system accompany numerous neurodegenerative diseases. TNF-alpha has been validated as a drug target with the development of the inhibitors Enbrel and Remicade (fusion antibodies) as prescription medications. Both, however, are large macromolecules that require direct injection and have limited brain access.

Adoptive cell therapy (ACT) uses cancer reactive T-cells to effectively treat patients. However, several obstacles inhibit the successful use of ACT for cancer treatment.  Current approaches for the expansion of T-cells may produce T-cells with a terminally differentiated phenotype that is associated with diminished anti-tumor activity and poor capacity for long-term persistence. Thus, there is a need for improved methods of obtaining an isolated population of effective T-cells for ACT. 

Neurofibromatosis type 1 (NF1) is a genetic disorder affecting 1 per 3000 individuals on average. Patients develop a variety of developmental benign and malignant pathologies. The most common tumors associated with NF1 are peripheral sheath tumors, including neurofibromas, optical gliomas, and malignant peripheral nerve sheath tumors.

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors. Point mutations in the KRAS gene most frequently affect amino acid position 12, resulting in the substitution of the native glycine (G) residue for other amino acids (e.g., aspartic acid (D), valine (V), cysteine (C) or arginine (R)).