December 7, 2022

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Cancer Research Blueprint: Challenges and Opportunities

Cancer Research Blueprint: Challenges and Opportunities



 

 

Cancer Research Blueprint: Challenges and Opportunities. On December 16, the top medical journal “CA-Cancer J Clin” of the American Cancer Society (ACS) published a review “Blueprint for Cancer Research: Key Gaps and Opportunities.”

The author has integrated conversations with more than 90 top cancer experts, highlighting current challenges, new opportunities and emerging areas of cancer research, and providing a blueprint for cancer research in the next decade.

 

Cancer Research Blueprint: Challenges and Opportunities

 

 

We are experiencing a cancer revolution. Screening, targeted therapy and immunotherapy, big data, algorithms and important new knowledge of cancer biology are changing the way we prevent, detect, diagnose, and treat cancer. These developments help us continue to achieve the goal of individualized cancer treatment.

 

From 1991 to 2017, the age-standardized cancer death rate in the United States continued to decline by 29%. Survival rates increase for most common cancers, and hematopoietic and lymphoid malignancies have the greatest long-term benefits. Recently, the survival rate of metastatic melanoma and non-small cell lung cancer has also increased significantly.

 

Despite these advances, we have not yet achieved the goal of eliminating cancer. The American Cancer Society (ACS) 2035 challenge goal is set to: reduce cancer mortality by 40% from the 2015 level. The success of this goal depends on continued research efforts to develop next-generation tools to understand, prevent and better control all types of cancer.

 

The breakthrough of cancer treatment depends on the further understanding of the etiology, genetics, biology and clinical heterogeneity of the tumor cell environment. ACS researchers have integrated the wisdom and insights of more than 90 top cancer experts to discover new opportunities and emerging fields in cancer research, and provide a blueprint for cancer research in the next decade.

 

This article focuses on new opportunities in four research areas, including: cancer screening and early detection, precision medicine (targeted therapy and immunotherapy), tumor heterogeneity/cellular plasticity/drug resistance, cancer modeling; and four Emerging areas of cancer research include: microbiome, metabolism, epigenetics and chromatin remodeling and metastasis.

 

 

 


1 Cancer screening and early detection

 

01 Current screening methods need to be improved

The most commonly used screening tests for early detection of cancer include breast, cervical, colorectal, lung, and prostate cancer. Each project has been successfully implemented, but has its strengths and weaknesses. It is essential for clinicians to find cheaper and simpler diagnostic solutions so that they can be most widely used. Suggest improvements in the following research areas:

  • Focus on research to reduce the breast imaging recall rate (7%-12%), and improve the ability to detect small lesions in dense breast tissue in a practical, cost-effective way;
  • Development of auxiliary screening tools to provide better prognostic information for breast ductal carcinoma in situ (DCIS);
  • Establish prognostic markers for aggressive prostate cancer;
  • Develop alternative or auxiliary screening tools for lung cancer (for example, a minimally invasive detection method to detect the biological activity of lung nodules identified by imaging).
  •  

02 Need to develop new screening methods

Among the 20 most common cancers in the United States, only 4 can reduce mortality by identifying early lesions, so there is an urgent need to develop such tools for other high-incidence malignancies. In discussions with experts, a number of high-priority research opportunities were identified, which can fill the current knowledge and technology gaps and pave the way for the development of new screening methods in the future:

  • Improve understanding of the molecular basis of cancer and precancerous lesions in the early stages;
  • Determine how the cellular and physical properties of the tumor microenvironment contribute to the transition from precancerous lesions to aggressive lesions;
  • Develop more sensitive and specific technologies for screening, early detection and risk stratification, and selectively invest in the most promising markers and technologies to accelerate clinical evaluation;
  • Redesign the clinical biomarker workflow to make it practical, reliable, and repeatable, and allow different analytes (circulating tumor DNA, circulating tumor cells, RNA, protein, metabolites, etc.) to be detected and quantified;
  • Explore the best ways to use artificial intelligence/machine learning and next-generation technologies (such as wearable devices) to help cancer screening and early detection.

 

 

 

 


2 Precision medicine: targeted therapy and immunotherapy

Since the National Institutes of Health’s precision medicine program was launched in 2015, great progress has been made in selecting the most suitable tumor interventions and treatments for individual patients. However, more research is still needed to fully realize the potential of precision medicine.

 

01  Development of new targets

Increase targeted therapies and discover abnormal pathways that directly affect all cancers.

  • Develop new anti-cancer drug targets and different chemical libraries to regulate the activity of enzymes and receptors;
  • Continue to use protein kinases, nuclear receptors and G protein coupled receptors as high-value targeted protein families;
  • Continue the preclinical and clinical evaluation of covalent Ras inhibitors;
  • Continue to explore strategies to inhibit the activity of irreversible targets including transcription factors; accelerate the study of epigenetic inhibitors for tumor treatment; explore direct targeting of non-coding regions of the genome (enhancers, promoters, insulators) or targeting non-coding The feasibility of RNA;
  • Functional verification of cancer targets, especially for common cancers or less common subtypes;
  • Clarify the biological and clinically relevant subtypes of common and uncommon cancers to determine the possibility of intervention, standardize morphology and molecular taxonomy.

 

02  Discover new opportunities for immunotherapy

Immunotherapy has brought a revolution in tumor treatment. Although immunomodulatory therapy has changed the clinical practice of some cancer types, it is necessary to continue to expand the scope of treatment.

  • Explore tumor heterogeneity and optimize antigen display;
  • Study the antigen display of metastatic cells and the role of vaccines in preventing metastasis;
  • Discover additional biomarkers (such as mismatch repair mutations, microsatellite instability) to determine which patients may respond to immunotherapy and which patients will experience serious adverse events;
  • Develop monoclonal antibodies to directly treat cancer and serve as site-specific carriers;
  • Develop methods of immune regulation to increase effector T cells and reduce regulatory T cells;
  • The focus of continuing clinical exploration of immune checkpoint inhibitors is to expand to different cancer types and unresponsive patients;
  • Continue to work hard to improve the effectiveness and efficiency of CAR-T cells and expand the target antigen library.

 

03  Accelerate the evaluation of comprehensive therapy

The latest results of the I-PREDICT clinical trial are encouraging (although only preliminary proof). Tumor DNA sequencing has found driver genes. The combined use of driver gene targeted therapy and immunotherapy can improve the prognosis of most patients.

  • Improved methods for simplifying preclinical research using in vivo and organoid systems;
  • Reduce barriers to combinatorial testing (for example, promote cooperation agreements between pharmaceutical companies);
  • Reduce the barriers for (adult) patients to participate in clinical trials and integrate genome sequencing into insurance coverage;
  • Develop and integrate interventions to reduce the barriers for underserved patients and racial and ethnic groups to obtain precision medicine;
  • Explore how to better manage the comorbidities of elderly cancer patients.

 

04  Data management

The personalized management method of cancer patients requires rapid analysis and integration of tumor DNA sequence information (and perhaps RNA and protein expression information) to inform personalized treatment plans and easily integrate with the extensive patient information contained in the electronic medical record. Such data flow requirements have been addressed in major cancer centers. Data storage, sharing, decision-making, and ownership are still key issues that continue to exist in oncology precision medicine research. Many of the challenges raised around big data involve infrastructure investment and operational concepts rather than research focus.

  • Clarify the role of public and private clinical patient information databases, serve individual patients, and provide resources for the creation and testing of hypotheses in research;
  • Clarify the role and rights of patients in contributing and controlling their clinical information;
  • Develop analytical tools and other strategies to reduce costs and make full use of available data on common and rare cancers;
  • Improve the process of extracting and interpreting data from patient health records that maintain patient privacy;
  • Develop methods for using data to better detect health gaps, and obtain and improve results;
  • Determine how to best use data across multiple sources, including the use of personal health equipment;
  • Improve the data quality and verification methods of medical health records, and give full play to the clinical utility of big data.

 

 

 

 


3  Tumor heterogeneity, cell plasticity and drug resistance

 

01  Develop methods for rapid screening of endogenous drug resistance and monitoring the emergence of acquired drug resistance

As more and more targeted drugs are used in combination with surgery, radiation and immunotherapy, precision medicine will rely more and more on complex methods to prove initial drug sensitivity, and rely on tools to monitor patient decline during treatment. Cancer cell changes in drug efficacy.

  • Accelerate the development of a system for monitoring patient drug resistance (ie liquid biopsy);
  • Develop calculations, artificial intelligence, in vitro methods and/or biomarker tests to predict endogenous resistance to chemotherapy and incorporate them into the patient’s treatment plan.

 

02  Promote the development of combination therapies to minimize disease recurrence

With the increasing use of a series of drugs targeting different molecular targets, cancer cells can use compensation mechanisms to develop drug resistance. These complex pathways are usually both the source of new drug targets and the location of drug-resistant mutations. Therefore, a comprehensive understanding of these cellular pathways will provide a key framework for realizing the vision of precision medicine.

  • Develop multiple generations of targeted inhibitors and study related molecular mechanisms of drug resistance;
  • Continue to evaluate complex pathways and how to modify them to achieve tumor suppression (for example, epigenetic regulation, apoptosis, aging, autophagy, translation control);
  • Continue to develop technologies to better evaluate the impact of tumor heterogeneity and tumor microenvironment on tumor evolution and drug resistance;
  • Learn more about cancer stem cells and their sensitivity to treatment, and their role in tumor recurrence and metastasis;
  • Have a deeper understanding of the factors that lead to mutation rate, genome instability and immune escape in tumor evolution;
  • A deeper understanding of the role and mechanism of non-coding and microRNA in cancer resistance.

 

 

 

 


4  Cancer modeling

We now have a complete catalog of gene variants of 33 cancer types, including 10 rare cancers. Armed with this basic information, we need to develop more preclinical models to capture the heterogeneity of diseases seen in humans.

More cancer type-specific models are also necessary to establish etiology, study cancer progression, and detect intervention measures. New preclinical metastasis models (which are the main cause of cancer death and have nothing to do with the type of cancer) are also urgently needed. The current experimental system rarely represents human metastatic disease.

 

01  Development of new cancer models

Prevent cancer

Although the use of drugs to control cancer has great potential, fulfilling this promise requires additional chemoprevention models, targeting common and rare cancer types. In addition, improved primary prevention models (for example, obesity) will improve the cross-evaluation of cancer initiation genetics and exposure.

Immunotherapy

It is necessary to perform preclinical modeling of the additional therapeutic effects of surgery, radiotherapy, and one or more forms of immunotherapy.

Tumor dormant/quiescent

For certain cancer types, such as high-grade serous ovarian cancer, there may be a longer period of remission, followed by recurrence of the disease. New modeling methods to clarify tumor dormancy mechanisms, pave the way for the development of biomarkers, predict and monitor disease recurrence, and design more effective treatment plans.

Basic cellular processes (such as autophagy, senescence and apoptosis)

Understanding the basic mechanisms that drive the fate of cancer cells after treatment can provide references for the development of new therapies for many cancer types.

Continue to use and integrate existing cancer model organs and human organs

Continue to build promising data to support the application of these three-dimensional systems in human cancer modeling, drug development and screening, and personalized medicine.

Systems biology model

Through calculation and mathematical analysis, including the integration of artificial intelligence and deep machine learning, expand the integration of systems thinking in cancer modeling.

 

 

 


5  Emerging areas of cancer research

The emerging areas of cancer research refer to those areas that are rapidly expanding and showing clinical prospects. Below, we will focus on four emerging areas to guide readers to have a deeper understanding of these rapidly developing areas, as well as the challenges and opportunities encountered in the laboratory and clinical trials.

 

01  Metabolism and cancer

Many aspects of metabolism affect cancer. At the cellular level, cancer reprograms part of the metabolic process to achieve effective nutrition in the absence of a microenvironment. This field used to focus on the metabolic conversion of aerobic glycolysis of cancer cells and how it affects tumor growth. Now it has expanded to study the various ways in which tumor cells and their surrounding microenvironment metabolism adapt to promote tumor growth and progression.

Some studies have shown that drug-resistant cells contain higher levels of ATP, which has led to the development of glycine hydrolysis inhibitors as anticancer drugs. In addition, there are new data that indicate that extracellular ATP levels may also increase significantly near tumor cells and contribute to the emergence of drug resistance.

Understanding how cancer cells are metabolized to affect their invasion behavior and treatment response, and understanding how cancer cells survive in an environment of hypoxia and nutrient deficiency will provide more effective cancer treatment methods. Rapamycin (sirolimus) and other mTOR inhibitors (such as everolimus, etc.) are excellent examples of basic research on cell energy balance to promote therapeutic innovation, which may lead to life-saving cancer progression.

  • Further explore the signal network of metabolic homeostasis at the biochemical, cellular and tissue levels, and the mechanism of how cancer cells destroy these pathways.
  • Study how oncogenic viruses change cell metabolism and affect cancer.
  • Identify key metabolic changes in the tumor microenvironment that affect the anti-tumor properties of immune cells.

People have a complicated and incomplete understanding of the relationship between metabolism, diet, exercise and cancer. Over the past decades, more and more evidence has shown that healthy diet and physical exercise play an important role in preventing cancer progression, reducing cancer risk, recurrence, and mortality from common malignancies. However, there is a lack of evidence-based lifestyle interventions for cancer patients, survivors, or patients at risk of cancer.

  • Determine how nutrition and physical activity affect the development of cancer, especially for rare cancer patients and stubborn cancer patients. 
  • A more comprehensive understanding of the molecular mechanisms of energy intake and lack of physical activity on cancer development, progression, recurrence and survival.
  • Establish evidence-based lifestyle interventions to promote and maintain behavior changes to achieve healthy weight control, healthy diet, and adequate levels of physical activity, and determine how to treat different cancers (or cancer recurrences) in clinical and community settings ) These strategies are best implemented among at-risk populations and cancer survivors.

Obesity is a global epidemic, is a risk factor for 13 different cancers, and is associated with cancer-related mortality in 15 cancers. Obesity is rarely caused by a slow metabolic rate, but by metabolic syndrome and insulin resistance. Obesity is associated with the accumulation of dyslipidemia, and is also associated with an increased risk of cancer (for example, postmenopausal breast cancer, endometrial cancer, colorectal cancer, and pancreatic cancer).

Although the epidemiological link between obesity and a variety of cancers is clear, at the biological level, the evidence for how or why obesity causes cancer is not complete. It is also interesting why many cancers are not related to obesity. Human clinical trials and pre-clinical (in vitro and in vivo) new evidence studies have shown that the interaction between adipose tissue and cancer seems to involve multiple types of organs and adipose tissues with different mechanisms.

Determine how the causes related to body composition-obesity (including the amount and distribution of adipose tissue), lean body mass, and body mass index affect cancer treatment, prognosis, and survival.

  • Conduct interdisciplinary research to determine the role of adipose tissue in the development of obesity-related cancers and the role of obesity-related chronic inflammation.
  • Develop new biological behavioral interventions to evaluate mechanisms and identify new biomarkers. Raise our understanding of how lifestyle factors affect cancer risk and cancer occurrence.
  • Doctors, nutritionists, kinesiologists, nurses, and pharmacists need professional development training in cancer research to promote interdisciplinary research in this field.

 

02  Microbiome

The microbiome is a complex ecosystem composed of bacteria, archaea, fungi, protozoa, worms and viruses, which live inside the human body. The microbiome significantly affects human health, and the imbalance (ecological disorder) of the microbiome is related to the development of cancer. Infectious factors and chronic inflammation are related to the development of cancer, and the concept of symbiotic microorganisms affecting cancer risk, diagnosis, treatment response and survival rate is relatively new.

Early research work focused on the impact of intestinal microbes on the occurrence of colorectal cancer. This field is rapidly expanding to study the impact of microbes in other anatomical parts on different cancer types.

There are many unknowns about how these microbial ecosystems (inside and outside the intestine, including the mouth, lungs, skin, and pancreas) affect cancer prevention, tumor development and progression, and treatment response. Because of the discovery that the composition of gut microbes can influence the response to cancer treatment (most prominently immunotherapy), the microbiome has become a hot topic in cancer research.

Many environmental factors (including diet, drugs, surgery, smoking, and sports activities) affect the microbial composition, which provides challenges and opportunities for research.

  • Explore microbial-mediated tumorigenesis and tumor suppression mechanisms, including the impact of specific microbes on tumor growth, metastasis, and response to treatment.
  • Explore the mechanisms by which the human microbiota controls local and systemic immunity. Study whether microorganisms and their toxins, adhesin and surface proteins can be used as vaccine targets.
  • Check whether and how the microbiome composition and anatomical parts promote anti-tumor immune responses and drug metabolism changes, and whether these can be used as prognostic or predictive biomarkers.
  • Study how microorganisms (viruses, yeasts, and protists) affect the development of cancer, and study how microorganisms respond to treatment.
  • Develop and implement safe and feasible intervention methods for microecological preparations (such as prebiotics and probiotics) in the clinic.
  • Further explore how lifestyle factors (diet, exercise, drinking, etc.) affect the microbiota, and how these changes affect cancer risk, recurrence and prognosis in adults and children.
  • Continue to study the interaction of the dietary microbiota to discover new clinical and public health methods; study how obesity and other major diet-related diseases affect children and adult cancer survivors.

 

03   Transfer

Most cancer deaths are caused by the metastasis of the primary tumor, which is a very complex biological process.

In the past few years, people have gained a more detailed understanding of the basic steps of cancer metastasis, including invasion, division, and colonization. The field of treatment of metastatic cancer is changing and expanding in exciting ways. For metastatic ER-positive breast cancer, CDK4/CDK6 inhibitors significantly improved progression-free survival.

The new combination of immunotherapy and chemotherapy is showing promise in patients with metastatic pancreatic cancer. Targeting tyrosine kinase inhibitors to treat brain metastases from melanoma, breast cancer, and lung cancer has encouraging results. The targeted vascular endothelial growth factor pathway is also used to manage metastatic renal cell carcinoma.

  • Establish new parameters to evaluate clinical trials of anti-metastatic therapies, including chronic dormancy related treatments and relapse prevention.
  • Improve the detection rate and resolution of micrometastasis.
  • To explore the influence of psychosocial factors of metastatic disease and the interaction between social and biological factors on recurrence and survival.
  • At the time of diagnosis, consider physical, emotional and economic factors to improve the management of transfer patients.

There are many research opportunities that can increase our basic understanding of cancer metastasis, which may pave the way for new targeted therapies to prevent the progression of early cancer and effectively treat advanced diseases:

  • Better understand the mechanism of metastatic cell formation.
  • Study the basis and impact of metastatic heterogeneity (genetic, epigenetic, and spatial).
  • Research and develop targeted drugs to treat or prevent metastatic disease and residual disease.
  • Clarify the molecular mechanisms of metastatic spread (for example, in blood vessels, extra blood vessels, in lymphatic vessels, along nerve fibers).
  • To clarify the molecular mechanisms of the metastatic potential of different tissues in tumors (ie, colonization of metastatic cells; tumor incubation period and outbreak; treatment resistance; hematopoietic cell changes in blood, bone marrow and future metastatic sites; and changes in immune activity and immune monitoring).
  • Clarify the role of immune monitoring in the diagnosis and elimination of disseminated micrometastasis; study the role of epigenetic regulation in inducing metastasis.

 

04  Epigenetics and chromatin remodeling

Epigenetics studies changes in gene expression without involving changes in DNA sequences, revealing the cellular mechanism of reversibly turning genes on and off.
Epigenetic control of gene expression is achieved through DNA methylation, histone modification (such as acetylation) or nucleosome chromatin re-simulation. Approximately half of human cancers have mutations in key genes that control chromatin remodeling, which may lead to inappropriate expression of key cellular control genes.

This provides an opportunity to discover, test and approve new targeted therapies. For example, aberrant DNA methylation patterns targeting 5-azacytidine (Vidaza; Celgene) and 5-aza-20-deoxycytidine (Dacogen; Otsuka America Pharmaceutical, Inc.) ) Has been approved by the FDA for the treatment of myelodysplastic syndrome. The second-generation analogues are undergoing clinical trials for the treatment of dysmyelocytosis syndrome and acute myeloid leukemia.

Although many studies support the role of histone acetyltransferase mutation or loss of function in cancer, the clinically used histone choline transferase inhibitors have not yet produced clinical success. Changes in the expression of histone deacetyltransferase are also associated with many cancers. Recently, it has been successfully used as an anti-cancer target (such as vorinostat).

The results of preclinical and clinical trials have shown that combining epigenetic therapy with other targeted therapies or combined with radiotherapy may improve the prognosis of cancer patients (especially lung cancer patients). Because only a few cancer patients have obtained lasting benefits from immunotherapy, the use of epigenetic reprogramming to enhance the effectiveness of immunotherapy is a promising area of ​​research.

With an in-depth understanding of the epigenetic mechanisms of cancer occurrence and development, its clinical effects have now been extended to discover new and targeted tools for treatment, diagnosis, prognosis, and prediction. For example, the DNA methylation status of a single gene promoter is increasingly being used to predict the treatment response and overall clinical outcome (prognosis) of multiple cancer types, including glioma, melanoma, and colorectal cancer. Epigenetic changes also provide hope for identifying biomarkers to assess cancer risk.

Although epigenetic events are important in cancer, they are not mutually independent or mutually exclusive events. Instead, they form a communication network that affects gene expression. For example, histone acetylation and ubiquitination drive the recruitment of DNA damage repair regulatory proteins.

The development of drugs targeting additional categories of epigenetic enzymes will successfully surpass the current epigenetic inhibitors, and will achieve higher specificity and better efficacy in precision medicine. Realizing the true potential of epigenetics and chromatin remodeling for cancer control requires a clearer understanding of their mechanism of action in tumorigenesis and the development of new technologies that accurately and sensitively detect chromatin and epigene changes.

  • Determine the range of epigenetic targets as effective drug targets for the development of new drugs.
  • Check the effectiveness of new epigenetic targets for challenging cancers with fewer treatment options, such as ovarian cancer.
  • Further explore the potential of epigenetics to provide prognostic information, diagnostic tools and treatment methods for a series of cancers.
  • Combined with the use of machine learning calculation methods to reveal the epigenetic pattern of cancer, it provides reference for the prognosis, diagnosis and treatment of cancer.

 

 

 


Cancer Research Blueprint: Challenges and Opportunities

Cancer Research Blueprint: Challenges and Opportunities

Cancer Research Blueprint: Challenges and Opportunities

Cancer Research Blueprint: Challenges and Opportunities

Cancer Research Blueprint: Challenges and Opportunities

Cancer Research Blueprint: Challenges and Opportunities


References:
1.Blueprint for cancer research:Critical gaps and opportunities. CA Cancer J Clin. 2020 Dec 16.

(source:internet, reference only)


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