Bio-TARGET

Conventional therapies such as surgery and radiotherapy are often ineffective in treating advanced malignant tumors while chemotherapy faces many challenges such as drug resistance during treatment, high risk of recurrence and severe side effects due to poor selectivity. Bio-TARGET was developed in response to the increasing incidence of cancer worldwide.

Bio-TARGET is an iteratively engineered bacterial-based bio-targeting system designed to reduce tumor resistance to chemotherapeutic agents and improve targeting ability. Its core mechanisms include RNA interference technology, engineered bacterial vectors and nanoparticle drug delivery. See Design for details.

Application Scenarios

The prevention of tumor with drug resistance:

In the early stage of tumor treatment, gene mutations or markers which are related to drug resistance are usually analyzed by biopsies of the tissue of patients or circulating tumor cells (CTCs), combined with molecular diagnostic techniques. Based on the analysis results, Bio-TARGET can pre-intervene potential drug resistance genes and conduct therapy with high targeting ability against these key resistance mechanisms while help reduce the risk of tumor cells developing drug resistance during chemotherapy, thus improving the effectiveness of treatment.

The treatment of tumor with drug resistance:

For patients who have developed drug resistance, Bio-TARGET offers an innovative treatment. By precisely targeting genes associated with drug resistance, Bio-TARGET can restore or enhance the sensitivity of tumor cells to chemotherapeutic agents, thereby improving treatment efficacy and reducing the side effects associated with conventional chemotherapy.

Inhibition of progression of tumor with drug resistance:

Bio-TARGET can be used to curb the further deterioration of tumors when drug resistance has been revealed and the disease has been an advanced stage. By precisely targeting key genes or proteins related to drug resistance, it inhibits the proliferation and metastasis of tumor cells and achieves the purpose of controlling the disease.

Synergistic application with other therapy:

Bio-TARGET can also be used in combination with other conventional treatments (e.g. surgery, radiotherapy, immunotherapy, etc.) to form a comprehensive treatment strategy. In this synergistic approach, the molecularly targeted therapies provided by Bio-TARGET will further enhance the effectiveness of other treatments, improve overall efficacy and reduce damages to healthy tissue.

Target Users

Cancer patients:

For patients suffering from tumors, Bio-TARGET offers a brand new therapeutic hope. It not only provides a means of preventing drug resistance of tumor before it occurs, but also effectively curtails resistance as it progresses and continues to play a therapeutic role after resistance occurs thus brings more personalized treatment services to patients.

Clinical doctors:

Aiming primarily at doctors dealing with patients with advanced tumors, Bio-TARGET offers a new solution that enhances the effectiveness of treatments while reduces suffering and side effects of patients.

Bio-tech Company:

Bio-TARGET has great commercial potential, particularly in the area of innovative development of drug and therapy which is suitable for biotech companies to develop and promote in depth.

Further design of experiments

The design of animal experiments

We propose to use C57BL/6 female mice for tumor seeding, grouping and drug administration. Observe the mental and dietary conditions of nude mice regularly. Weight the mice, measure lengths and widths of the tumor nodules (a × b) to obtain V = π/6 × ab2 (mm3), and plot the tumor growth curve of the change in tumor volume against time on an arithmetic coordinate. The tumor tissue was exfoliated intactly at the end of the experiment and the tumor inhibition rate was calculated.

Clinical Trials

We will strictly follow the 4 phases in process of clinical study that must be undergone before a drug can be admitted in China to ensure that the safety and efficacy of Bio-TARGET are fully validated.

Phase I clinical trial: to evaluate the safety, tolerability and preliminary pharmacokinetic profile of Bio-TARGET in humans.

Phase II clinical trial: to further evaluate the efficacy of Bio-TARGET and determine the optimal dose based on the confirmation of safety in the Phase I clinical trial.

Phase III clinical trial: to validate the efficacy and safety of Bio-TARGET in a larger group of subjects and compare it to existing therapies.

Phase IV clinical trials (post-market monitoring): to continue to monitor long-term efficacy, safety and adverse reactions of the drug after it is marketed to provide the basis for drug improvement and patient management.

Construction of mathematical model

We plan to develop an algorithm for assessing chemotherapy resistance targets, combined with artificial intelligence to provide personalized treatment plans for patients requiring chemotherapy. When acquiring tumor sequencing data of the patient, a resistance typing strategy is first constructed from mutation profiles and chemotherapy resistance databases (e.g. OncoKB, GDSC, etc.). For example, for lung cancer patients, it may be possible to analyze the sensitivity of these mutations to different chemotherapeutic agents and infer tumor resistance to chemotherapy based on EGFR mutations or ALK fusion genes. At this point, we will introduce AI models to predict the drug resistance patterns of different patients by training a large amount of clinical data, thus achieve more accurate typing and diagnosis.

Based on the typing of drug resistance the system will be able to recommend combination treatment options. For example, if a patient carries the TP53 mutation and is resistant to platinum-based chemotherapeutic agents, the system may recommend the use of anti-PD-1/PD-L1 immunotherapy in combination with a PARP inhibitor, relying on the DNA repair defects of the patient's tumor for targeted treatment. By integrating different therapies, the therapeutic efficacy is maximized.

In addition, we will focus on multi-target analysis and improved RNAi target selection. In the process of drug resistance typing, the mutation and high expression of key genes will be used as the basis for target selection. For example, for breast cancer patients, HER2 high expression and BRCA mutation may become key targets, and inhibition of these genes by using RNAi can be more effective in dealing with drug resistance. To further optimize the effects, in the future we hope to optimize RNAi therapy by selecting multiple targets through a weighted algorithm and using AI models to predict the synergistic effects of inhibiting multiple genes at the same time.

The implementation of the weighting algorithm is one of the keys to this system. Through the multi-targets optimization algorithm, the system can adjust the weighting coefficients of RNAi targets in patient data with different mutation statuses, and gradually optimize the effect of inhibiting multiple genes at the same time. As the model learns and validates, the AI is able to find the best combination of targets, which in turn improves the therapeutic effects. This series of steps will help us cover tumor typing, drug resistance assessment, target selection and treatment strategy all around, and ultimately achieve personalized precision therapy by continuously improving the algorithm through clinical data feedbacks.

Safety & Ethics

Bio-TARGRT has a long way to go to become an available strategy of treatment against some of the world's fatal cancers. We would like to think of the implementation page as a holistic interpretation of the project from the past to present, and ultimately to the desired future path we anticipate. Ethical and safety considerations are crucial during the promotion of the project. Safety concerns the prospective attitude of all stakeholders towards Bio-TARGRT, and ethics ensures that our work is not only scientifically robust, but also morally sound and makes good, responsible social sense.

We have never neglected the importance of safety, and we know that safety inside and outside the lab bench is equally important. While maximizing the safety of the design in the project (link safety), we also paid particular attention to the privacy and intellectual property protection of all stakeholders. By writing and signing informed consent forms for interviews and encrypting data, we maintained privacy and security throughout the project. Additionally, as the project progressed, we came to realise that the first step to achieving success was to prevent our ideas from being leaked to potential competitors or any people that could replicate our results. We have learnt and developed a chain of intellectual property protection and filing ideas belonging to Bio-TARGRT, and although the project is still in the pre-seed stage of business, it is certain that after jamboree we will form all our modules for overall validation and expand the types of related cancers. We are also actively pursuing intellectual property applications and patent protection barriers.

Ethical enquiry and feedbacks form a large part of the JLU-NBBMS iHP. We have developed a sizeable scale of ethical thinking by talking and learning from all the ethical experts we have access to. Ethical principles in the fields of clinical trial ethics, medical ethics, animal ethics, technology ethics, and social ethics were incorporated throughout the design of the experiments while activities in HP and education part. In the end, we have developed physical ethical outcome documents that strongly prove and demonstrate that the progress of Bio-TARGRT is ethical, responsible, and genuinely beneficial to the world. Of course, we will never stop here. Ethics is such a complex system, and due to rapid advances, the ethical guidelines governing synthetic biology are not always comprehensive. Potential dual uses, rapidly developing cutting-edge technologies, socio-ethical considerations for oncology patients... The pursuit of ethical considerations related to biotechnology projects seems to be an endless task, but JLU-NBBMS will never stop moving forward ethically and will always analyze potential ethical issues, refine ethical inquiries and implement ethical guidelines in every process of project promotion.

Enter the Markets

Access to Markets

To bring Bio-TARGET to the global market, it is critical to obtain market access approval. This process involves passing through a rigorous drug approval process with regulatory agencies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the China National Drug Administration (NMPA). We will demonstrate the safety, efficacy and quality of Bio-TARGET through comprehensive clinical trials, including upfront safety tests, Phase I-III human clinical trials and post-market surveillance. We will also develop strategies to adapt to the regulatory requirements of different regions to ensure that the product can enter the global market successfully.

Production and distribution

The development of a scalable manufacturing process is the key to ensure a stable supply of Bio-TARGET. Manufacturing facilities must follow Good Manufacturing Practices (GMP) to ensure safety and consistency of efficacy from batch to batch. We will establish a robust supply chain that connects production centers to our distribution network to ensure that Bio-TARGET can be efficiently delivered to various healthcare systems. In addition, working with logistics providers, we will ensure that Bio-TARGET is distributed globally, with special attention to product stability during transport and storage.

Clinical Collaboration

Establishing strong partnerships with hospitals, clinics and cancer treatment centers are critical to incorporating Bio-TARGET into standard treatment protocols. These partnerships will facilitate the use of Bio-TARGET in clinical settings and evaluate its efficacy in real-world conditions. We will provide training programs for healthcare professionals to ensure that they are able to use Bio-TARGET correctly, and we will provide ongoing clinical support to ensure the optimized outcomes of patients. In addition, collaborations with research organizations will enable us to provide continuous feedbacks and improvements based on clinical results and evolving cancer treatments.

The acceptance of Bacterial-Based Cancer Therapy

Although bacterial therapies have shown great potential in the field of scientific research, their acceptance by the public and the medical community remains a key issue. Traditionally, bacteria are often regarded as pathogens rather than methods of treatments. Therefore, we need to enhance the public's trust and understanding of bacterial therapies through extensive scientific outreach, presentation of clinical trial data, and sharing of successful cases (as what we have done, see Education for details). In addition, communication with healthcare organizations, doctors and patients is crucial in future applications to ensure that they fully understand the mechanisms, safety and efficacy of the therapy.

The safety of Bacterial-Based Cancer Therapy

Safety is the issue that must be rigorously considered before any medical therapy is marketed. Although we are using modified attenuated Salmonella, there are still potential biosafety risks, such as bacterial escape and increased drug resistance which is led by genetic mutations. To ensure the safety of patients, we need to conduct exhaustive safety assessments, including animal experiments, human trials and long-term follow-up observations. At the same time, a strict production, quality control and regulatory system should be established to ensure the safety and stability of bacterial therapies.

The effectiveness of tumor with multiple drug resistance

The mechanisms of tumors with multiple drug resistance are a major challenge in current cancer treatment. Although our Bio-TAGET system screens drug-resistant targets genes through clinical sample collection and mathematical modeling and is designed to target the key drug -resistant genes in tumor cells with drug resistance, we still need to face the challenges of tumor heterogeneity, the efficiency of drug delivery, and multiple drug resistant mechanisms of tumor cells in practical applications. In order to improve the effectiveness in tumors with multiple drug resistance, we need to continuously optimize the design of Bacterial-Based Cancer Therapy, such as adjusting the selection of RNAi targets, enhancing bacterial penetration in tumor tissues, and combining with other therapeutic means (e.g., immunotherapy, radiotherapy, etc.) to form an integrated therapeutic strategy.

Prospect

With our deeper understanding of bacterial therapies and the continuous optimization of their safety and efficacy, we believe that this innovative therapy will be able to bring benefits to more cancer patients. It not only improves the effectiveness and targeting ability of treatment, but also reduces systemic damages. It can bring new therapeutic hope to patients who have developed resistance to conventional therapies as well.