Dr. Zhou,
Cardiothoracic Surgery
Zhejiang Provincial People's Hospital
According to the World Health Organization (WHO), cancer ranks as the leading cause of death globally. We did a questionnaire survey on patients and their families at the hospital to learn more about the general situation of cancer patients and the present cancer medications considering the urgent need to develop new drugs with good efficacy, low price, and minimal adverse effects. Through interacting with doctors, oncology experts, and PhDs from biotech companies, we gradually optimize and clarify the project's choice of experimental signaling pathways, the present cancer medications, identification of targets, efficacy validation content, screening drugs range and market for drug screening systems.
The World Health Organization（WHO） reports that nearly 10 million deaths (or nearly one in six) in 2020 are caused by cancer[1]. Anti-cancer therapies limit cancer cell spread and metastasis, but have adverse effects like allergic reactions, anemia, and stomach and intestine damage. Despite these issues, the urgent need for new anticancer medications makes their development crucial.
Signaling pathways are crucial for biological activity and disrupting them can lead to cancerous tumors. The Hippo signaling system, impacted by stomach, colon, and lung cancers. Therefore, precise and efficient therapy choices for particular cancer types can be increased by creating and using tailored medications that aim abnormalities in the Hippo signaling system. Serine/threonine protein kinases 3 and 4 (STK3 and STK4) are essential elements of the Hippo signaling pathway. According to research investigations, STK3 and STK4 in vitro knockdown and pharmacological inhibition prevent AML cells from proliferating. A different class of drugs that target the Hippo pathway are currently being tested in human trials. In patients with advanced malignant mesothelioma and other NF2 mutant tumors, the YAP/TEAD inhibitor VT3989 was well tolerated and exhibited long-lasting anti-tumor responses, according to the findings of a Phase I trial directed by scientists at The University of Texas MD Anderson Cancer Center.
High-throughput screening technologies have transformed drug development in recent years, speeding up the discovery of lead drugs by enabling scientists to test tens of thousands of compounds in a relatively short amount of time. High-throughput screening supports the development of new medications with high sensitivity, precision, and efficiency by assisting in the discovery of promising molecules.
We discovered through the questionnaire poll that while health insurance already covers the price of treating cancer, there are still some people who cannot pay the ongoing expenses. Additionally, the current medications have drawbacks like user difficulty and adverse effects on the body. We need to conduct more drug research in order to achieve the objectives of low cost and minimal adverse effects in order to ameliorate the aforementioned condition.
a. The questionnaire's respondents are primarily middle-aged and elderly over 36, with the highest proportion of lung cancer, with 46% in advanced and 34% in middle stages, identifying through personal discomfort and medical checkups.
b. The cost of cancer treatment is high. The findings reveal that even if health insurance can cover a portion of the cost of treatment, most consumers still view it as a sizable financial burden.
c. According to patients and their families, 33% of the cancer therapy medications currently available have some negative effects, and 32% believe that some injectable medications are difficult to use on one's own. There is still a need to investigate improved programs and medications for the treatment of cancer because most patients had an unfavorable opinion of the current cancer treatments.
Dr. Zhou,
Cardiothoracic Surgery
Zhejiang Provincial People's Hospital
Through our conversation with Dr. Zhou, we learnt that while the majority of cancer medications are presently covered by Medicare, there are still some expensive medications that are not yet included. For instance, there are currently no medications available that are associated to the hippo signaling pathway that are reimbursed by Medicare. This phenomenon shows that more work must be done on these medications in order to be able to satisfy the criteria for medical reimbursement.
Dr. Sun
Deputy Director、Department of Oncology
Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine.
We spoke with Dr. Sun because we have long been perplexed by the sluggish progress of cancer medication research. The progression-free period can last up to three years, or even closer to four years, due to the necessity to create new medications for targets that are resistant to the targeted drugs. This is an issue with present targeted drugs, she stated to us. She also demonstrated how it may be harder to treat a drug's side effect if it is connected to the target of therapeutic significance. The aforementioned arguments demonstrate the need for novel medicine development. The detailed views are listed below:
a. Targeted drug resistance is currently an issue, necessitating the development of new medications against the resistance target, also known as the golden target, so extend the progression-free duration to three years or even near to four years. For instance, medications for lung cancer (alectinib, imatinib) must be tested for the target patients' tolerance, constantly improved, and fought against the modified cells to eventually produce a more substantial effect.
b. It will be harder to treat a side effect if it is connected to the therapeutic target of the drug. For instance, some drugs are taken with skin lesions (i.e., skin ulcers), which suggests that the drug is acting in the patient's body and is more effective. There is still hope that adverse effects including those that influence appetite and harm the liver can be reduced.
Mr. Fu
Research area: Drug discovery and development
Mr. Fu suggested that drug candidates from drug screening are often sold to companies in the form of patents, but it is usually necessary to provide information on the site of action of the drug and the target. This point gives us a clearer understanding of the workflow in the early stage of drug discovery and development and motivates us to further improve our drug screening system (mutation experiments) and clarify the mode of cooperation between researchers and pharmaceutical companies. To try to meet these requirements, we followed up our experiments by mutating the sites predicted by Autodock and then performing in vitro pull-down experiments. The experimental results verified the sites where CX6258 interacts with MST2. This will help us patent these three amino acid sites of MST2 and increase the commercial value of the project.
We know that the hippo signaling pathway controls a wide range of biological functions, including cell division, survival, differentiation, and proliferation. Increased activity of YAP/TAZ, which is connected to malignancies, excessive cell proliferation, and cell invasion, results from dysregulation of the Hippo pathway. Therefore, it is possible to develop and use drugs against the abnormalities of the hippo signaling system, but we are still unable to identify the specific targets. Therefore, a request for help was initiated to Ms. Song.
Mrs. Song
Associate Professor
School of Life Science and Technology, Shanghai Jiao Tong University
Mrs. Song responded to our concerns about the target selection by saying that it is appropriate to choose MST2-STRN3 because of the role MST2 plays in the phosphokinase activity of the hippo signaling pathway. Mrs. Song suggested that we could perform high-throughput screening using the Alpha Screen technology. Mrs. Song stated that even though this system has a high throughput, high efficiency, and high sensitivity, it is also susceptible to ambient light, strong light, and photobleaching, necessitating several screenings by pull-down. The specific concepts are as follows:
a. By preventing the activity of YAP in the nucleus, the threonine protein kinase MST2 prevents cell growth and prevents cell death. By recruiting and encouraging the dephosphorylation of MST1/2, STRN3 is a crucial regulatory subunit of protein phosphatase 2A (PP2A), which activates YAP and shuts down Hippo signaling. This results in the overexpression of oncogenes and, ultimately, the over proliferation of cancer cells. The downstream proteins of the hippo pathway will have more gene loci that they regulate and may have more adverse consequences if they are employed as targets, decreasing the accuracy of the pathway. We therefore think that choosing MST2-STRN3 as a target should be worthwhile given the significance of MST2's phosphokinase activity in the hippo pathway.
b. After Mrs. Song understood our high-throughput screening experiment’s principle, she suggested us to use Alpha Screen technology. Because this system is exactly the principle of utilizing the interaction between proteins, it matches our project.
c. Alpha technology is a versatile method for detecting biomarkers and studying intracellular molecular interactions. It can detect a wide range of substances, has a homogeneous system, fast and stable results, and high sensitivity. It can also detect crude biological extracts without fluorescent labeling. However, its major limitations include sensitivity to light, optical signal degradation due to oxygen trapping, and one-way signal detection. Its screening results must therefore be further confirmed using pull-down iterations over several iterations.
Lei Zhang
Professor
School of Life Science and Technology, Shanghai Jiao Tong University
We spoke with pertinent specialists to better understand drug effect validation and the use of Drosophila model animals in drug effect validation. Currently, mice and Drosophila are the primary methods used to validate efficacy. Our project's primary study area is biopharmaceuticals, and Drosophila makes a wonderful experimental subject because it is inexpensive, rapidly evolving, and capable of large-scale screening, which is currently not conceivable in mice. And he suggested that the new use of old drugs has the advantages of avoiding patents, reducing toxicity and so on.
a. Because of its conserved nature, quick development rate, low cost, and capacity for extensive screening, Drosophila is a good experimental subject for cancer research. Drosophila species should be chosen based on the study's objectives. There are still many specific questions about conserved pathways that need to be answered in mice.
b. Candidate small compounds must first bind to the target proteins, then undergo site prediction, modification, and functional testing on the mouse before being tested on additional malignancies to confirm function.
c. Old medications are new, more flow-based, process-oriented, and focused on avoiding patents, toxicity reduction, and having a more sensitive and accurate affinity.
Dr. Li
HANSOH PHARMA
We spoke with Dr. Li to identify the market and application path for our drug screening technology. We discovered from him that drug testing systems can be used for both drug testing services and drug testing goods. Additionally, he advised that we strive to construct a drug screening management system, a one-stop solution for managing drug screening data, due to the ongoing expansion and development of the present drug screening business.
A. The use of innovative drug screening techniques can speed up and lower the cost of developing new treatments by more rapidly and efficiently weeding out compounds that are pharmacologically active from a large library of chemicals. It is important to examine since it has broad implications.
B. It is advised to set up a drug screening management system that can offer a compound resource library, pharmacological screening model library, screening experimental data storage and management services for national, local, and municipal level, university research institutions and drug enterprises, and other drug screening units, and provide a one-stop solution for managing drug screening data.
C．Drug testing can be divided into drug testing services and drug testing products depending on the information provided. Drug testing services are typically provided by companies that produce drug testing technology for laboratories, research units, or other businesses. Drug testing products are typically created by companies that produce analytical instruments, rapid detection equipment, and consumables.
Starting from the technology of our project itself, our team members discussed that if we make a commercial module, we can make the service and technology as the main product. So, we conducted an in-depth investigation of this module.
Mr. Chen
Head of Technology Incubator
He introduced us to the business operation models of major technology incubators in the current market, and gave us a positive attitude towards our idea, thinking that our project could try to do shared consulting and shared service boards. In addition, he also suggested that if we want to improve the content of the business board, we can go to see more successful business cases. The following is the main operation model:
(1) Shared facilities
A representative example is the China Science and Technology Innovation College. Through cooperation, large and expensive equipment is taken out and "shared", which can effectively solve the "pain point" and difficult problem of the lack of hardware conditions for major innovation projects.
(2) Shared Space
Provide a free and open collaborative environment, encourage cross-border exchanges, let ordinary people's needs or ideas become products, and commercialize some of the products with market prospects. Sell various components to creators, as well as sell products invented by creators.
(3) Shared Services
For example, to make profits through cultural and artistic experiences, consumption of cultural goods, etc., and to promote the development of the cultural industry.
(4) Shared Consulting
Provide one-on-one technical counseling and support for entrepreneurs to help them overcome technical difficulties
We have enhanced the project in every way based on the findings of the expert interviews and questionnaire surveys. We discovered that the current anti-cancer drugs have drawbacks like high side effects and complicated methods of use, and that new drugs must be developed to solve these problems in the practical application market through questionnaire surveys of hospital patients and their families as well as interviews with Drs. Sun and Zhou. We were more certain about selecting the hippo signaling pathway as a cancer treatment target after taking into account Ms. Song's recommendation and the findings of the associated literature search, and we ultimately found the MST2-STRN3 target. After chatting with Ms. Song, we discovered that we could perform high-throughput screening using the Alpha Screen technology, and that photobleaching, bright light, and ambient light all had an impact on the Alpha Screen reporter screening system. Ms. Song added that further studies are necessary to further validate the screening results. When we questioned Mr. Zhang about experiments involving Drosophila, he responded that Drosophila had to be used as a test subject because mice could not be thoroughly vetted. Through our discussion with Dr. Li, we were able to determine the potential and future course of the drug screening market. With the help of Mr. Chen, we decided to try to do shared consulting and shared service boards.