Biomarkers have become an essential component of Alzheimer disease (AD) research

Deep learning in cancer pathology

AI Biomarker Discovery

Creation of an automated platform for the determination of predicting biomarkers in clinical trials of oncological drugs.

This page of software developers is dedicated to AI, software, bioinformatics, biophysics, development of algorithms for checking 3D structures, genomic analysis, genomic atlas, physical parameters of the interaction of biological molecules obtained by calculation, comparison with experimental data. Home page https://www.binomlabs.com/

Biomarker development concept

Affinity-targeting schemes for protein biomarkers

Identification of Cancer Biomarkers
Our team proposes the development of an innovative method for the determination of biomarkers by processing the database with the developed software.

The excitement created by the development of new techniques for the global molecular analysis of tumors (DNA sequences, Genom Cancer Atlas) has led some scientists to predict that the end of histopathology is in sight. Indeed, with the advent of targeted therapies, it can be argued that we are in the midst of a paradigm shift in which the most important part of the work-up of a cancer sample is the identification of molecular targets, rather than histopathologic diagnosis.

For example, it is now appreciated that histopathologically distinct cancers may harbor the same gain-of-function mutation in the serine/threonine kinase BRAF, a component of the RAS signaling pathway. In principle, all of these diverse "BRAFomas" are candidates for treatment with BRAF inhibitors.

However, clinical studies have shown that the effectiveness of BRAF inhibitors (for reasons that remain to be determined) vary widely depending on histologic subtype: hairy cell leukemias with BRAF mutations typically show sustained responses, melanomas respond transiently, and colon carcinomas respond little, if at all, emphasizing the value of morphologic diagnosis. An example of a treatment based entirely on molecular features is the use of checkpoint inhibitors in patients with recurrent and metastatic tumors based on defects in mismatch repair genes and not on histologic features, which we mentioned earlier.

The method proposed by us suggests the development (and refinement of existing) targeted drugs, taking into account the change in genetic information in the case of oncological diseases for each individual patient.

Analysis of the effect of each individual mutation in the protein on affinity for targeted drugs.
Determination of the genomic variability of each individual patient and the selection of targeted drugs, taking into account the personal variability of the gene code.
Analysis of biochemical pathways, taking into account the oncological variability of protein functions, gene expression, involvement of inhibitors, targeted drugs.
Identification of key points that will make it possible to judge the direction of biochemical reactions, the benefits of using one or another targeted therapy.

Introduction to an existing diagnostic problem.

What do we offer?

the drug/list of drugs
target molecule/molecules,
the proteins involved into biochemical reactions

4.construction of a biochemical scheme.

A new biomarker analysis resource for clinical research.

Determination of all protein modifications involved in biochemical reactions 4

Calculation of affinity,
shift of thermodynamic equilibrium in biochemical systems

Identification of the category of patients according to the effectiveness of therapy depending on the genome and protein expression.

AI Solutions

Identification of biomarkers and categories of patients

How are biomarkers qualified for drug development?

Preliminary detection

Stages

Precision Medicine | Pfizer

Drug development

precision medicine example, precision medicine group, precision medicine advantages, precision medicine company, astrazeneca precision medicin, eprecision medicine wikipedia

“Precision medicine is a healthcare approach that utilises molecular information (genomic, transcriptomic, proteomic, metabolomic, etc),.

digital biomarkers software

Innovations in personalized medicine using AI solutions

We propose to develop a platform that will predict the outcome of oncology clinical trial depending on predictive biomarkers. The platform is expected to optimize:

1) identification of key players in biochemical pathways

2) the patient population for the I-III phase study by identifying biomarkers within the existing early data (Clinical data such as age, gender, body mass index (BMI), tumor location, tumor size, symptoms, complications, surgical treatment, operation time, preoperative blood biochemistry data) and considering the standard of care to maximize the likelihood of success.

Early clinical trial data

input

Projection to real world data

output

The platform is expected to allow the use of predictive biomarkers that are typically not measured in clinical care.

What stage is the AI platform among all other clinical research studies

We propose the development of an automatic platform, which is shown in the figure and allows you to receive data before the start of the first clinical phase of the trial.
Within the phase I–IV paradigm of drug development, biomarker discovery may start in phase I trials but is often limited to preliminary exploration or proof-of-concept because of the small sample sizes. Phase II studies are generally the platform for initial biomarker discovery studies and identify markers to be evaluated further in phase III trials. The most informative biomarker studies are part of phase III trials because their larger sample sizes afford more power and because they randomize patients to the drug regimen of interest and a control arm.

Development of a cancer through stepwise acquisition of complementary mutations.

Molecular basis of cancer: Role of Genetic and Epigenetic Alterations

Nonlethal genetic damage lies at the heart of carcinogenesis.
A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage(i.e. tumors are clonal)

Alterations in DNA are heritable, being passed to daugter cells, and thus all cells within an individual tumor share the same set of mutations that were present at the moment of transformation.

Four classes of genes are the principal targets of cancer -causing mutations:

growth-promoting proto-oncogenes,
growth-inhibiting tumor supressor genes,
regulate programmed cell death (apoptosis) genes,
responsible for DNA repair genes

Carcinogenesis results from the accumulation of complementary mutation in a stepwise fashion over time.

Malignant neoplasms have several phenotypic attributes referred to as cancer hallmarks:

local invasiveness
ability to form distant metastases,
genomic alterations,
change the expression genes
impart a malignant phenotype

Mutations that contribute to the acquisition of cancer hallmarks are referred to as driver mutations.
Loss-of-function mutations in genes that maintain genomic integrity appear to be a common early step on the road to malignancy, particularly in solid tumors.

Molecular Profiles of Tumors: The Future of Personalized Medecine

Until recently, molecular studies of tumors involved the analysis of individual genes. Hower, the past few years have seen the introduction of revolutionary technologies that can rapidly sequence an entire genome; assess epigenetic modifications genome-wide; quantify all of the RNAs expressed in a cell population and others.

These advances have enable the systematic sequencing and cataloging of genomic alterations in various human cancers, much of it within a large consortium sponsored by the National Cancer Institute called the Cancer Genome Atlas (TCGA).

One goal of these analyses is to identify therapeuicaly "actionable" genetic lesions. Such approaches are particularly applicable to tumors such as lung carcinomas, which are genetically diverse are require a "personalized" approach if targeted therapy is to succeed. Other clinical useful information is obtained.
The observed pattern mutations can be used ti identify microsatellite instability.

Traditional medical treatments have been designed as a “one-size-fits-all” approach.
But while these treatments can be effective for some patients, they may not be for others.

Precision medicine takes into account individual differences in genes, environments and lifestyles. In this way, doctors can select treatments that are most likely to help patients based on a more complete picture and understanding of their disease or ailment.

Precision medicine focuses on targeted, personalized care using big data. The objective of precision medicine is to make diagnosis of disease or illness, treatment therapies, and prevention more personalized, proactive, predictive and precise.

Advances in Precision Medicine have already led to powerful new discoveries and several new treatments that are tailored to specific characteristics, such as a person’s genetic makeup, or the genetic profile of an individual’s tumor. This is helping transform the way we can treat diseases such as cancer: Patients with breast, lung, and colorectal cancers, as well as melanomas and leukemias, for instance, routinely undergo molecular testing as part of patient care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects.

What are the features of personalized medicine?

1. What is precision medicine for?
Precision medicine, sometimes known as "personalized medicine" is an innovative approach to tailoring disease prevention and treatment that takes into account differences in people's genes, environments, and lifestyles.
2. What are the fields in precision medicine?
Precision medicine brings together innovations in fields such as genomics, metabolomics, biomedical data sciences and environmental sciences. It utilizes technologies such as mobile health, imaging, big data, artificial intelligence, social engagement and networking.
3. Why is precision medicine recommended?
With precision medicine, we are now in the position to make treatment decisions not simply based on the specific cancer but on the genes that make up that cancer. By examining the DNA of a patient's tumor, we can identify the cancer-causing genes that make cancers grow.
4. Is precision medicine AI?
The convergence of artificial intelligence (AI) and precision medicine promises to revolutionize health care. Precision medicine methods identify phenotypes of patients with less‐common responses to treatment or unique healthcare needs.

Types and role of biomarkers in the clinical practice

According to the biomarker's classification of the FDA-NIH Biomarker Working Group, there are different types based on their main clinical application: diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers (Fig. 1)

Each type of biomarker may provide complementary information about the disease or the intervention under consideration and potentially contribute to improve diagnosis, prognosis and clinical outcomes.

Diagnostic biomarker
The biomarkers of this category are used to confirm the presence of a disease or medical condition. In this context, diagnostic biomarkers may play an important role to reach a precise diagnosis, identifying patients with a disease and facilitating the classification of patients with the same type of diagnosis to personalize drug treatments, therefore, increasing the efficacy of the therapeutic response. Thus, beyond its potential role as a diagnostic tool, these biomarkers may also be useful in prognosis and in predicting treatment outcome

Monitoring biomarker
This category includes biomarkers measured at different time points for assessing presence, status or extent of a disease or medical condition

Pharmacodynamic/response biomarker
Pharmacodynamic/response (PD) biomarkers present a vast spectrum of applications from the early phases of the discovery research to the clinical trials, and later, during the clinical practice. This type of biomarker may be defined as “a biomarker used to show that a biological response occurred in an individual exposed to a medical product or an environmental agent”

As a proof of mechanism, PD biomarkers indicate that the drug acts on its key target, such as the evaluation of receptor occupancy or monitoring ligand disposition. The results collected in this respect facilitate the construction of pharmacokinetic-pharmacodynamic models in later stages.

Fig.1. Types of biomarkers based on their main clinical application.

Comprehensive Pharmacology
2022, Pages 693-724

Let's go to Example!

Change of thermodynamic equilibrium on the example of BRAF-MEK interactions.

BRAF is a notable oncoprotein within the MAPK signaling pathway, which involves phosphorylation cascades leading to protein translation and transcription factor regulation important for cell proliferation. BRAF has a propensity to be mutated in a significant number of cancers, and in about 50% of melanomas in particular. About 90% of BRAF mutations associated with cancer contain a single point mutation of valine to glutamic acid at residue 600 (BRAF^V600E), which triggers an active protein conformation in the absence of activation loop phosphorylation . Because of the prevalence of BRAF^V600E mutations in melanoma, this mutant form of the kinase has emerged as an important drug target for melanoma therapy. BRAF^V600E-selective inhibitors such as vemurafenib (PLX4032) and dabrafenib have been approved by the FDA based on extended overall survival in patients with metastatic BRAF^V600E melanoma.

However, almost all patients develop drug resistance within about 6 months of treatment through diverse mechanisms, but predominantly through reactivation of the MAPK pathway, for example through mutation of upstream RAS or downstream MEK.

Small chemical molecule (inhibitor of BRAF)

Biomarkers can measure whether cancer has progressed or if it is likely to respond to treatment.

Adenosine 5'-triphosphate

B-Raf proto-oncogene, serine/threonine kinase

Mitogen-activated protein kinase kinase and MAP2K, is a kinase enzyme that phosphorylates mitogen activated protein kinases (MAPKs), ERK, p38 and JNK.

Biochemical scheme with interaction of wild-type BRAF proteins

Biochemical scheme with interaction of mutation BRAF proteins

Biochemical scheme with interaction of mutation BRAF
and wt BRAF proteins

Conventions adopted in the study.
Abbreviations.

The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma.

What drugs are BRAF inhibitors?

Vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi) are drugs that attack the BRAF protein directly. These drugs can shrink or slow the growth of tumors in some people whose melanoma has spread or can't be removed completely.

What does BRAF stand for?
BRAF (v-raf murine sarcoma viral oncogene homolog B1) is a serine/threonine protein kinase that plays a critical role in the RAS-RAF-MEK-ERK mitogen activated protein kinase (MAPK) cell signalling pathway.

What does BRAF mean in cancer?
What is a BRAF mutation? A BRAF mutation is a spontaneous change in the BRAF gene that makes it work incorrectly. A mutation causes the gene to turn on the protein and keep it on, which means certain cells get ongoing signals to keep dividing and no instructions on when to stop. This can lead to development of a tumor.

What cancers have a BRAF mutation?
BRAF mutation is seen in melanoma, papillary thyroid carcinoma (including papillary thyroid carcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal carcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia.

General sheme of biochemical reations pathway involving proteins BRAF and MEK

List of Biomarkers - Profiling biomarkers in cancer

Types of biochemical schemes subject to thermodynamic calculation

1. Biochemical reactions considering interacting wild-type BRAF and MEK proteins and ATP molecules.
2. Calculation of thermodynamic equilibrium in the interaction of wild-type BRAF and MEK proteins, as well as ATP molecules and one type "Small chemical molecule" (S.C.M)
3. Calculation of thermodynamic equilibrium during the interaction of a wild-type protein and a mutant form of a protein, as well as ATP molecules and one type "Small chemical molecule"
- The influence of each individual mutation of the BRAF protein on the change in the thermodynamic equilibrium of the system will be studied.
4. Study of the effect of a selected small chemical molecule upon interaction with the mutant BRAF protein, the wild-type MET protein, and ATP molecules

Symbol:___BRAF
Name:_____B-Raf proto-oncogene, serine/threonine kinase
Synonyms:_BRAF1
UniProtKB:_Swiss-Prot:P15056

This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion.

Figure 1.Scheme of biochemical reactions taking into account BRAF and MEK proteins, as well as ATP.

This scheme will be investigated taking into account the addition of small chemical molecules, ATP, mutations from the Cancer Atlas.

The influence of each mutation and the targeted drug on the shift of biochemical equilibrium for dimers, homotetramers, heterodimers and others will be revealed.

Each link will be examined separately for stability, entropy change

Figure 2. Thermodynamic equations for further research

General sheme of biochemical reations pathway involving proteins BRAF and MEK, taking into account the addition of small chemical molecules.

Figure 2.Scheme of biochemical reactions taking into account BRAF and MEK proteins, as well as ATP and Small Chem.Mol.

This scheme demonstrates the biochemical scheme, taking into account the addition of medical drugs to be researched.

Targeted Therapy Drugs for Melanoma Skin Cancer

Targeted Therapy Drugs for Incidence of melanoma has been constantly growing during the last decades. Although most of the new diagnoses are represented by thin melanomas, the number of melanoma-related deaths in 2018 was 60,712 worldwide (Global Cancer Observatory, 2019). Until 2011, no systemic therapy showed to improve survival in patients with advanced or metastatic melanoma. At that time, standard of care was chemotherapy, with very limited results. The identification of BRAF V600 mutation, and the subsequent introduction of BRAF targeting drugs, radically changed the clinical practice and dramatically improved outcomes. In this review, we will retrace the development of molecular-target drugs and the current therapeutic scenario for patients with BRAF mutated melanoma, from the introduction of BRAF inhibitors as single agents to modern clinical practice. We will also discuss the resistance mechanisms identified so far, and the future therapeutic perspectives in BRAF mutated melanoma.

How structural analysis is done?

See illustrative examples of calculations, comparison of structures, download the mathematical apparatus.

Next, it is good to familiarize yourself with the rules for checking the correctness of the PDB with many different examples.

Structural analysis is carried out by observation of the real structure, on a model of the structure created on some scale, and by the use of mathematical models.

What is structure comparison tool for now?

How do you test protein structure?
The most common method used to study protein structures is X-ray crystallography. With this method, solid crystals of purified protein are placed in an X-ray beam, and the pattern of deflected X rays is used to predict the positions of the thousands of atoms within the protein crystal.
What are 3 ways of assessing protein quality?
Currently, the structural similarity between two proteins is measured by the root-mean-square-deviation (RMSD) in their best-superimposed atomic coordinates.
We propose a completely new method for checking the PDB of structures.
Which chemical methods are used for structure determination?
There are a variety of methods for structure determination, such as X-ray crystallography, cryo-electron microscopy, NMR spectroscopy, etc. The explanation of molecular geometry, as well as the electronic form of the target molecule, is essential when a chemical structure is determined.
What is RMSD between two structures?
Background: The root mean square deviation (rmsd) between corresponding atoms of two protein chains is a commonly used measure of similarity between two protein structures. The smaller the rmsd is between two structures, the more similar are these two structures.

Find out how relevant is the comparison of RMSD to determine the correctness of building a structure.
What is structure comparison?
Structure comparisons are also fundamental parts of methods for protein structure prediction and prediction of function from structure. Structure comparison methods have three main components: the score function, the alignment method, and the background distribution used for assessing significance of comparisons.
What is the most common structural analysis method?
The most commonly used numerical approximation in structural analysis is the Finite Element Method. The finite element method approximates a structure as an assembly of elements or components with various forms of connection between them and each element of which has an associated stiffness.

Familiarize yourself with modern methods for checking PDB structures

Determining the pathways of biochemical processes

The fraction of non-dissociated molecules after the reaction and concentration protein-ligand complex
Entropy Change . The case of a one-dimensional normal distribution

3.Entropy Change . The case of multinormal normal distribution
4.Constant dissociation
5. Enthalpy change
6. The thermal dissociation
7. Potential energy of electrostatic interaction between all amino acid residues taken in pairs
8. Potential energy of the lower vibrational level.
9. Potential energy of the upper vibrational level.
10.Step-by-step verification of the PDB file structure.

Additional calculated parameters:

What do we have for obtaining information about the direction of a biochemical reaction?

Analysis of the biochemical complex N1

We investigate how the physical parameters characterizing system N1 (wtBRAF) change when the system transitions to state N6 and N3 (mutBRAF)

Each protein complex has its own physical parameters that determine the interaction:

The analysis of changes in these values makes it possible to detect the formation and decay of biological complexes, as well as to rank biological complexes according to their degree of affinity.

This is followed by routine construction of biochemical schemes and affinity calculations.

Settlement nodes of the biochemical scheme given earlier involving proteins BRAF and MEK

cancer biomarkers examples fda-approved cancer biomarkers list cancer biomarkers ppt cancer biomarker discovery and validation

[(BRAF-BRAF)]+S.C.M.+S.C.M._____________________[(BRAF-S.C.M.)(BRAF-S.C.M.)]

[(BRAF-S.C.M.)]+[(BRAF-S.C.M.)]__________________[(BRAF-S.C.M.)(BRAF-S.C.M.)]

3D4Q

Cancer biomarker discovery and validation

3Q4C

4MNE

cancer biomarker development and discuss the issues in clinical translation of cancer biomarkers.

[BRAF-MEK]+2[ATP] _____________________[(BRAF-ATP)(MEK-ATP)]

[(BRAF-ATP)]+[(MEK-ATP)] ________________[(BRAF-ATP)(MEK-ATP)]

[(BRAF-ATP)(MEK-ATP)]+[S.C.M.]________________[(ATP-BRAF-S.C.M.)(MEK-ATP)]

[(S.C.M.-BRAF-ATP)]+[(MEK-ATP)]_______________[(ATP-BRAF-S.C.M.)(MEK-ATP)]

[(mBRAF-ATP)(MEK-ATP)]+[S.C.M.]________________[(ATP-mBRAF-S.C.M.)(MEK-ATP)]

[(S.C.M.-mBRAF-ATP)]+[(MEK-ATP)]_______________[(ATP-mBRAF-S.C.M.)(MEK-ATP)]

[mBRAF-MEK]+2[ATP] _____________________[(mBRAF-ATP)(MEK-ATP)]

[(mBRAF-ATP)]+[(MEK-ATP)] ________________[(mBRAF-ATP)(MEK-ATP)]

The rapid detection of cancer-specific biomarkers is of great importance

[(BRAF-ATP)(MEK-ATP)]

[BRAF-MEK]

[(BRAF-ATP)]

[(MEK-ATP)]

Use of biomarkers in cancer research and treatment

[(BRAF-ATP)(MEK-ATP)]

[(ATP-BRAF-S.C.M.)(MEK-ATP)]

[(MEK-ATP)]

[(S.C.M.-BRAF-ATP)]

detection and quantification of cancer biomarkers.

Early diagnosis significantly reduces cancer-related mortality

1UWH//The complex of wild type B-RAF and BAY439006.
1UWJ //The complex of mutant V599E B-RAF and BAY439006.
2FB8//Structure of the B-Raf kinase domain bound to SB-590885
3C4Q//B-Raf Kinase in Complex with PLX4720

Данный раздел постепенно наполняется информацией о структурных данных биологического комплекса B-RAF и малых химических молекул