Below, our major finished or ongoing drug development projects are described. For further details regarding drug development, please contact Ivan Randelovic, PhD.
DEVELOPMENT OF TARGETED THERAPIES AGAINST HUMAN TUMORS HARBORING MUTATIONS OF KRAS ONCOGENE
In this project, KINETO Lab Ltd. continued development of KRAS targeting small molecules, whereby will be tested novel tyrosine kinase inhibitors alone and in combination with farnesyltransferase inhibitors on tumor cells carrying different KRAS mutations (G12C, D, V) on in vitro and in vivo tumor models. Moreover, optimization of Ras inhibitors identified from a fragment-based molecular library will be performed for therapy efficacy improvement.
HORIZON 2020 – EUROPEAN TRAINING NETWORK: SMALL MOLECULE DRUG CONJUGATES FOR TARGETED DELIVERY IN TUMOR THERAPY (MAGICBULLET::RELOADED)
KINETO Lab Ltd. continued its membership in the ”MAGICBULLET::RELOADED” international research consortium continued from „MAGICBULLET” built for studying the application of drug conjugates in targeted tumor therapy.
Despite the continuing development of new and more efficient treatments, cancer remains the second cause of premature death worldwide. Multi-faceted interdisciplinary research efforts in industry and academia on different aspects of cancer have provided a knowledge basis for the development of novel therapeutic approaches. An ideal therapeutic agent would be a “magic bullet” that only kills the target cells. This ETN initiative with the title Magicbullet::Reloaded refers to Ehrlich’s bold idea and builds on the previous experience of the ETN MAGICBULLET (2015-2018, grant agreement No. 642004).
The ETN Magicbullet::Reloaded will expand the field of investigation from peptide-drug conjugates (PDCs) to small molecule-drug conjugates (SMDCs) with a special focus on drugs capable to stimulate tumor immune responses and overcome resistance to immune-therapy. The consortium has been substantially expanded to perfectly address the needs of the new research direction. The planned ETN will design and synthesize an array of SMDCs (including PDCs), also targeting less investigated tumor antigens, investigate their pharmacokinetic behavior, their implication on the immune system, as well as their tumor selectivity and antitumor activity.
MAGICBULLET::RELOADED under the Marie Skłodowska-Curie grant agreement No 861316. www.magicbullet-reloaded.eu
DEVELOPMENT OF BIOMEDICAL RESEARCH AND SERVICE CAPACITY AND EXPLORE NEW TYPES OF ANTICANCER THERAPEUTIC SOLUTIONS
In this project, KINETO Lab intends to expand its existing tissue culture and animal-based infrastructure so that it can continually be able to isolate larger amount of antibodies several times a year, from the hybridomas created by its own earlier development or from its cells from its academic and industrial partners. The antibodies so obtained are then marketed in various technical solutions (laboratory diagnostic kits, molecular biology reagents, immunohistochemical techniques, etc.).
Testing of new active substances, including therapeutic antibodies, requires the use of better preclinical models. These include molecular biology methods, cell and tissue culture techniques, and animal experiments. This is also the case in oncology. Patient-derived tumor xenografts (PDTX), when implanting a direct surgical sample into specific mice, represent a much better representation of the original tumor because of not only the tumor cells but also their environment are transplanted. The second major objective of the project is to develop such specific models from the least manageable tumor types, subsequent basic and R&D.
In addition, thirdly, with the help of the models, KINETO Lab develops new types of antibodies that are specifically active in tumor vessels, for diagnostic and therapeutic use. Identification of endothelial markers is a novel therapeutic target that can reduce the side effects of anticancer treatments and increase their effectiveness on tumors.
DEVELOPMENT OF DIAGNOSIS AND TARGETED THERAPY OF RASOPATHIES
KRAS is one of the most frequently mutated oncogene in human cancer with an outstanding incidence rate among the most prevalent cancers such as colon and rectum cancer (40%), lung adenocarcinomas (30%) and pancreatic cancer (80%). Moreover, with smaller frequency, other tumor types (myeloma multiplex, head and neck- and breast cancer) display KRAS mutations as well. KRAS mutant human cancers are more aggressive and less sensitive to classical chemotherapeutic agents.
In clinical oncology the new paradigm is the introduction of the molecular targeted therapies exploiting the characteristic genetic alterations of the tumors which is frequently mutation of oncogenes. However, the efficacy of targeted therapies (i.e. anti-EGFR agents) is critically determined by the KRAS mutational status of the tumor, as mutated KRAS leads to resistance to these expensive therapies. Therefore, the mutant oncogenic KRAS in human cancer emerged as arguably the most outstanding issue in clinical oncology that should guide the future of R&D activities.
HORIZON 2020 – EUROPEAN TRAINING NETWORK: PEPTIDE-DRUG CONJUGATES FOR TARGETED DELIVERY IN TUMOR THERAPY (MAGICBULLET)
KINETO Lab Ltd. is member of HORIZON 2020 Marie Skłodowska-Curie Actions MAGICBULLET” international research consortium built for studying the application of drug conjugates in selective tumor therapy.
Many tumor cells are characterized by the overexpression of certain antigens. Molecules that specifically recognize these structures are suitable as homing devices in tumor therapy. Conjugation of anticancer drugs with such a delivery vector targeting tumors would be a “magic bullet” according to the Nobel laureate Paul Ehrlich. Antibody-drug conjugates (ADC) technology have already been approved for anticancer therapy. However, ADCs have limitations with respect to tumor penetration, high manufacturing costs, and require challenging conjugation chemistry. Peptide-drug conjugates have a high drug loading capacity, easily penetrate tissue, and can be cost efficiently prepared in a homogenous form with straightforward and well-defined conjugation chemistry.
The focus of the European Training Network (ETN) MAGICBULLET is on chemistry-driven approaches toward conjugates between peptides as delivery vectors that recognize tumors and anticancer drugs in order to selectively fight cancer, a topic with a high demand of research activities. The ETN allows to develop and validate an array of new peptide-drug conjugates combining either known tumor-specific peptides or newly discovered tumor-homing peptides with potent cytotoxic drugs. The tumor-selective peptides are designed for cellular uptake mediated either by endocytosis or by cell-penetrating peptides.
The combination of an array of tumor-selective peptides targeting different receptors and different uptake mechanisms with diverse antitumor drugs acting on different cellular targets is a powerful strategy to minimize potential risks on healthy cells and increase the efficacy toward tumors. Because the number of receptors on tumor cells is limited, the combination of different target peptide–drug conjugates may enhance the bioactivity. The influence of the treatment schedule of such combination therapy on the antitumor activity will also be evaluated.
The consortium of the ETN MAGICBULLET brings together interdisciplinary expert knowledge in tumor biology, drug discovery, biochemistry, pharmacology, cell biology, organic chemistry, peptide chemistry, synthetic chemistry, medicinal chemistry, spectroscopy, conformational analysis, and computational chemistry. The training program focuses on multidisciplinary research to explore and validate molecular targets for innovative treatment or investigations on the molecular mechanisms in organ-specific metastatic growth processes. It aims at scientific multilingualism and relies on concerted learning, a combination of introductory training, hands-on learning “on the bench”, teaching by peers, and training in additional skills. This high complementarity is required for the different scientific tasks in the development pipeline.
The ETN MAGICBULLET is a tool that can:
- identify, modify, and validate tumor-selective peptides for known and new cell surface receptor targets (e.g. integrins, Gonadotropin-releasing hormone receptors, CD13, VEGFR, cadherins);
- study different linker systems for release of the anticancer payloads at the appropriate site;
- conjugate known and new anticancer agents or drugs to tumor-selective peptides;
- investigate the biological activity in vitro and in vivo to demonstrate their efficacy.
MAGICBULLET under the Marie Skłodowska-Curie grant agreement No 642004. www.magicbullet.de