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Thursday, October 28, 2021

Targeted drug delivery

From Wikipedia, the free encyclopedia

Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult and the reduced ability to adjust the dosages.

Targeted drug delivery systems have been developed to optimize regenerative techniques. The system is based on a method that delivers a certain amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the required plasma and tissue drug levels in the body, thereby preventing any damage to the healthy tissue via the drug. The drug delivery system is highly integrated and requires various disciplines, such as chemists, biologists, and engineers, to join forces to optimize this system.

Background

In traditional drug delivery systems such as oral ingestion or intravascular injection, the medication is distributed throughout the body through the systemic blood circulation. For most therapeutic agents, only a small portion of the medication reaches the organ to be affected, such as in chemotherapy where roughly 99% of the drugs administered do not reach the tumor site. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. For example, by avoiding the host's defense mechanisms and inhibiting non-specific distribution in the liver and spleen, a system can reach the intended site of action in higher concentrations. Targeted delivery is believed to improve efficacy while reducing side-effects.

When implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease.

Increasing developments to novel treatments requires a controlled microenvironment that is accomplished only through the implementation of therapeutic agents whose side-effects can be avoided with targeted drug delivery. Advances in the field of targeted drug delivery to cardiac tissue will be an integral component to regenerate cardiac tissue.

There are two kinds of targeted drug delivery: active targeted drug delivery, such as some antibody medications, and passive targeted drug delivery, such as the enhanced permeability and retention effect (EPR-effect).

Targeting Methods

This ability for nanoparticles to concentrate in areas of solely diseased tissue is accomplished through either one or both means of targeting: passive or active.

Passive Targeting

In passive targeting, the drug's success is directly related to circulation time. This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system (RES), thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time. To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time.

Active Targeting

Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to. Researchers can then utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand. The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles.

Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging. Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process.

Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive. Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH. Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is hypoxia, which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors.

By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug. It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue. However, an emerging field known as nanotoxicology has concerns that the nanoparticles themselves could pose a threat to both the environment and human health with side effects of their own. Active targeting can also be achieved through peptide based drug targeting system.

Delivery vehicles

There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic, biodegradable, and must avoid recognition by the host's defense mechanisms.

Liposomes

Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules. Though liposomes can vary in size from low micrometer range to tens of micrometers, unilamellar liposomes, as pictured here, are typically in the lower size range, with various targeting ligands attached to their surface, allowing for their surface-attachment and accumulation in pathological areas for treatment of disease.

The most common vehicle currently used for targeted drug delivery is the liposome. Liposomes are non-toxic, non-hemolytic, and non-immunogenic even upon repeated injections; they are biocompatible and biodegradable and can be designed to avoid clearance mechanisms (reticuloendothelial system (RES), renal clearance, chemical or enzymatic inactivation, etc.) Lipid-based, ligand-coated nanocarriers can store their payload in the hydrophobic shell or the hydrophilic interior depending on the nature of the drug/contrast agent being carried.

The only problem to using liposomes in vivo is their immediate uptake and clearance by the RES system and their relatively low stability in vitro. To combat this, polyethylene glycol (PEG) can be added to the surface of the liposomes. Increasing the mole percent of PEG on the surface of the liposomes by 4-10% significantly increased circulation time in vivo from 200 to 1000 minutes.

PEGylation of the liposomal nanocarrier elongates the half-life of the construct while maintaining the passive targeting mechanism that is commonly conferred to lipid-based nanocarriers. When used as a delivery system, the ability to induce instability in the construct is commonly exploited allowing the selective release of the encapsulated therapeutic agent in close proximity to the target tissue/cell in vivo. This nanocarrier system is commonly used in anti-cancer treatments as the acidity of the tumour mass caused by an over-reliance on glycolysis triggers drug release.

Micelles and dendrimers

Another type of drug delivery vehicle used is polymeric micelles. They are prepared from certain amphiphilic co-polymers consisting of both hydrophilic and hydrophobic monomer units. They can be used to carry drugs that have poor solubility. This method offers little in the terms of size control or function malleability. Techniques that utilize reactive polymers along with a hydrophobic additive to produce a larger micelle that create a range of sizes have been developed.

Dendrimers are also polymer-based delivery vehicles. They have a core that branches out in regular intervals to form a small, spherical, and very dense nanocarrier.

Biodegradable particles

Biodegradable particles have the ability to target diseased tissue as well as deliver their payload as a controlled-release therapy. Biodegradable particles bearing ligands to P-selectin, endothelial selectin (E-selectin) and ICAM-1 have been found to adhere to inflamed endothelium. Therefore, the use of biodegradable particles can also be used for cardiac tissue.

Artificial DNA nanostructures

The success of DNA nanotechnology in constructing artificially designed nanostructures out of nucleic acids such as DNA, combined with the demonstration of systems for DNA computing, has led to speculation that artificial nucleic acid nanodevices can be used to target drug delivery based upon directly sensing its environment. These methods make use of DNA solely as a structural material and a chemical, and do not make use of its biological role as the carrier of genetic information. Nucleic acid logic circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus such as a specific mRNA have been demonstrated. In addition, a DNA "box" with a controllable lid has been synthesized using the DNA origami method. This structure could encapsulate a drug in its closed state, and open to release it only in response to a desired stimulus.

Applications

Targeted drug delivery can be used to treat many diseases, such as the cardiovascular diseases and diabetes. However, the most important application of targeted drug delivery is to treat cancerous tumors. In doing so, the passive method of targeting tumors takes advantage of the enhanced permeability and retention (EPR) effect. This is a situation specific to tumors that results from rapidly forming blood vessels and poor lymphatic drainage. When the blood vessels form so rapidly, large fenestrae result that are 100 to 600 nanometers in size, which allows enhanced nanoparticle entry. Further, the poor lymphatic drainage means that the large influx of nanoparticles are rarely leaving, thus, the tumor retains more nanoparticles for successful treatment to take place.

The American Heart Association rates cardiovascular disease as the number one cause of death in the United States. Each year 1.5 million myocardial infarctions (MI), also known as heart attacks, occur in the United States, with 500,000 leading to deaths. The costs related to heart attacks exceed $60 billion per year. Therefore, there is a need to come up with an optimum recovery system. The key to solving this problem lies in the effective use of pharmaceutical drugs that can be targeted directly to the diseased tissue. This technique can help develop many more regenerative techniques to cure various diseases. The development of a number of regenerative strategies in recent years for curing heart disease represents a paradigm shift away from conventional approaches that aim to manage heart disease.

Stem cell therapy can be used to help regenerate myocardium tissue and return the contractile function of the heart by creating/supporting a microenvironment before the MI. Developments in targeted drug delivery to tumors have provided the groundwork for the burgeoning field of targeted drug delivery to cardiac tissue. Recent developments have shown that there are different endothelial surfaces in tumors, which has led to the concept of endothelial cell adhesion molecule-mediated targeted drug delivery to tumors.

Liposomes can be used as drug delivery for the treatment of tuberculosis. The traditional treatment for TB is skin to chemotherapy which is not overly effective, which may be due to the failure of chemotherapy to make a high enough concentration at the infection site. The liposome delivery system allows for better microphage penetration and better builds a concentration at the infection site. The delivery of the drugs works intravenously and by inhalation. Oral intake is not advised because the liposomes break down in the Gastrointestinal System.

3D printing is also used by doctors to investigate how to target cancerous tumors in a more efficient way. By printing a plastic 3D shape of the tumor and filling it with the drugs used in the treatment the flow of the liquid can be observed allowing the modification of the doses and targeting location of the drugs.

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Targeted therapy

From Wikipedia, the free encyclopedia
 
Patients and their diseases are profiled in order to identify the most effective treatment for their specific case.

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy). Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy (and thus distinguished from chemotherapy, that is, cytotoxic therapy). However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

Another form of targeted therapy involves the use of nanoengineered enzymes to bind to a tumor cell such that the body's natural cell degradation process can digest the cell, effectively eliminating it from the body.

Targeted cancer therapies are expected to be more effective than older forms of treatments and less harmful to normal cells. Many targeted therapies are examples of immunotherapy (using immune mechanisms for therapeutic goals) developed by the field of cancer immunology. Thus, as immunomodulators, they are one type of biological response modifiers.

The most successful targeted therapies are chemical entities that target or preferentially target a protein or enzyme that carries a mutation or other genetic alteration that is specific to cancer cells and not found in normal host tissue. One of the most successful molecular targeted therapeutic is Gleevec, which is a kinase inhibitor with exceptional affinity for the oncofusion protein BCR-Abl which is a strong driver of tumorigenesis in chronic myelogenous leukemia. Although employed in other indications, Gleevec is most effective targeting BCR-Abl. Other examples of molecular targeted therapeutics targeting mutated oncogenes, include PLX27892 which targets mutant B-raf in melanoma.

There are targeted therapies for lung cancer, colorectal cancer, head and neck cancer, breast cancer, multiple myeloma, lymphoma, prostate cancer, pancreatic cancer, melanoma and other cancers.

Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy.

Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response and prevent the development of drug resistance.

The definitive experiments that showed that targeted therapy would reverse the malignant phenotype of tumor cells involved treating Her2/neu transformed cells with monoclonal antibodies in vitro and in vivo by Mark Greene's laboratory and reported from 1985.

Some have challenged the use of the term, stating that drugs usually associated with the term are insufficiently selective. The phrase occasionally appears in scare quotes: "targeted therapy". Targeted therapies may also be described as "chemotherapy" or "non-cytotoxic chemotherapy", as "chemotherapy" strictly means only "treatment by chemicals". But in typical medical and general usage "chemotherapy" is now mostly used specifically for "traditional" cytotoxic chemotherapy.

Types

The main categories of targeted therapy are currently small molecules and monoclonal antibodies.

Small molecules

Mechanism of imatinib

Many are tyrosine-kinase inhibitors.

Small molecule drug conjugates

  • Vintafolide is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor. It is currently in clinical trials for platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study (TARGET trial) in non-small-cell lung carcinoma (NSCLC).

Serine/threonine kinase inhibitors (small molecules)

See also: Serine/threonine kinase

Monoclonal antibodies

Main article: Monoclonal antibody therapy

Several are in development and a few have been licensed by the FDA and the European Commission. Examples of licensed monoclonal antibodies include:

Many antibody-drug conjugates (ADCs) are being developed. See also ADEPT (antibody-directed enzyme prodrug therapy).

Progress and future

In the U.S., the National Cancer Institute's Molecular Targets Development Program (MTDP) aims to identify and evaluate molecular targets that may be candidates for drug development.
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War on cancer

From Wikipedia, the free encyclopedia

The "war on cancer" is the effort to find a cure for cancer by increased research to improve the understanding of cancer biology and the development of more effective cancer treatments, such as targeted drug therapies. The aim of such efforts is to eradicate cancer as a major cause of death. The signing of the National Cancer Act of 1971 by United States president Richard Nixon is generally viewed as the beginning of this effort, though it was not described as a "war" in the legislation itself.

Despite significant progress in the treatment of certain forms of cancer (such as childhood leukemia), cancer in general remains a major cause of death 40+ years after this war on cancer began, leading to a perceived lack of progress and to new legislation aimed at augmenting the original National Cancer Act of 1971. New research directions, in part based on the results of the Human Genome Project, hold promise for a better understanding of the genetic factors underlying cancer, and the development of new diagnostics, therapies, preventive measures, and early detection ability. However, targeting cancer proteins can be difficult, as a protein can be undruggable.

History

Main article: History of cancer

National Cancer Act of 1971

External video
Richard Nixon presidential portrait.jpg
video icon The Long War on Cancer, Retro Report

The war on cancer began with the National Cancer Act of 1971, a United States federal law. The act was intended "to amend the Public Health Service Act so as to strengthen the National Cancer Institute in order to more effectively carry out the national effort against cancer". It was signed into law by President Nixon on December 23, 1971.

Health activist and philanthropist Mary Lasker was instrumental in persuading the United States Congress to pass the National Cancer Act. She and her husband Albert Lasker were strong supporters of medical research. They established the Lasker Foundation which awarded people for their research. In the year of 1943, Mary Lasker began changing the American Cancer Society to get more funding for research. Five years later she contributed to getting federal funding for the National Cancer Institute and the National Heart Institute. In 1946 the funding was around $2.8 million and had grown to over $1.4 billion by 1972. In addition to all of these accomplishments, Mary became the president of the Lasker Foundation due to the death of her husband in 1952. Lasker's devotion to medical research and experience in the field eventually contributed to the passing of the National Cancer Act.

The improved funding for cancer research has been quite beneficial over the last 40 years. In 1971, the number of survivors in the U.S. was 3 million and as of 2007 has increased to more than 12 million.

NCI Director's Challenge

In 2003, Andrew von Eschenbach, the director of the National Cancer Institute (who served as FDA Commissioner from 2006-2009 and is now a Director at biotechnology company BioTime) issued a challenge "to eliminate the suffering and death from cancer, and to do so by 2015". This was supported by the American Association for Cancer Research in 2005 though some scientists felt this goal was impossible to reach and undermined von Eschenbach's credibility.

John E. Niederhuber, who succeeded Andrew von Eschenbach as NCI director, noted that cancer is a global health crisis, with 12.9 million new cases diagnosed in 2009 worldwide and that by 2030, this number could rise to 27 million including 17 million deaths "unless we take more pressing action."

Harold Varmus, former director of the NIH and director of the NCI from 2010 to 2015, held a town hall meeting in 2010 in which he outlined his priorities for improving the cancer research program, including the following:

  1. reforming the clinical trials system,
  2. improving utilization of the NIH clinical center (Mark O. Hatfield Clinical Research Center),
  3. readjusting the drug approval and regulation processes,
  4. improving cancer treatment and prevention, and
  5. formulating new, more specific and science-based questions.

Renewed focus on cancer

Recent years have seen an increased perception of a lack of progress in the war on cancer, and renewed motivation to confront the disease. On July 15, 2008, the United States Senate Committee on Health, Education, Labor, and Pensions convened a panel discussion titled, Cancer: Challenges and Opportunities in the 21st Century. It included interviews with noted cancer survivors such as Arlen Specter, Elizabeth Edwards and Lance Armstrong, who came out of retirement in 2008, returning to competitive cycling "to raise awareness of the global cancer burden."

Livestrong Foundation

The Livestrong Foundation created the Livestrong Global Cancer Campaign to address the burden of cancer worldwide and encourage nations to make commitments to battle the disease and provide better access to care. In April 2009, the foundation announced that the Hashemite Kingdom of Jordan pledged $300 million to fund three important cancer control initiatives – building a cutting-edge cancer treatment and research facility, developing a national cancer control plan and creating an Office of Advocacy and Survivorship. The Livestrong Foundation encourages similar commitments from other nations to combat the disease.

Livestrong Day is an annual event established by the LAF to serve as "a global day of action to raise awareness about the fight against cancer." Individuals from around the world are encouraged to host cancer-oriented events in their local communities and then register their events with the Livestrong website.

21st Century Cancer Access to Life-Saving Early detection, Research and Treatment (ALERT) Act

The US Senate on 26 March 2009 issued a new bill (S. 717), the 21st Century Cancer Access to Life-Saving Early detection, Research and Treatment (ALERT) Act intended to "overhaul the 1971 National Cancer Act." The bill aims to improve patient access to prevention and early detection by:

  1. providing funding for research in early detection,
  2. supplying grants for screening and referrals for treatment, and
  3. increasing access to clinical trials and information.

Obama-Biden Plan to Combat Cancer

During their 2008 U.S. presidential campaign then Senators Barack Obama and Joe Biden published a plan to combat cancer that entailed doubling "federal funding for cancer research within 5 years, focusing on NIH and NCI" as well as working "with Congress to increase funding for the Food and Drug Administration." Their plan would provide additional funding for:

  • research on rare cancers and those without effective treatment options,
  • the study of health disparities and evaluation of possible interventions,
  • and efforts to better understand genetic factors that can impact cancer onset and outcomes.

President Obama's 2009 economic stimulus package includes $10 billion for the NIH, which funds much of the cancer research in the U.S., and he has pledged to increase federal funding for cancer research by a third for the next two years as part of a drive to find "a cure for cancer in our time."In a message published in the July 2009 issue of Harper's Bazaar, President Obama described his mother's battle with ovarian cancer and, noting the additional funding his administration has slated for cancer research, stated: "Now is the time to commit ourselves to waging a war against cancer as aggressive as the war cancer wages against us." On 30 September 2009, Obama announced that $1 billion of a $5 billion medical research spending plan would be earmarked for research into the genetic causes of cancer and targeted cancer treatments.

Cancer-related federal spending of money from the 2009 Recovery Act can be tracked online.

World Cancer Campaign

The International Union Against Cancer (UICC) has organized a World Cancer campaign in 2009 with the theme, "I love my healthy active childhood," to promote healthy habits in children and thereby reduce their lifestyle-based cancer risk as adults. The World Health Organization is also promoting this campaign and joins with the UICC in annually promoting World Cancer Day on 4 February.

Progress

Though there has been significant progress in the understanding of cancer biology, risk factors, treatments, and prognosis of some types of cancer (such as childhood leukemia) since the inception of the National Cancer Act of 1971, progress in reducing the overall cancer mortality rate has been disappointing. Many types of cancer remain largely incurable (such as pancreatic cancer) and the overall death rate from cancer has not decreased appreciably since the 1970s. The death rate for cancer in the U.S., adjusted for population size and age, dropped only 5 percent from 1950 to 2005. As of 2012, WHO reported 8.2 million annual deaths from cancer. Heart disease (including both Ischaemic and hypertensive) accounted for 8.5 million annual deaths. Stroke accounted for 6.7 million annual deaths. 

There is evidence for progress in reducing cancer mortality. Age-specific analysis of cancer mortality rates has had progress in reducing cancer mortality in the United States since 1955. An August 2009 study found that age-specific cancer mortality rates have been steadily declining since the early 1950s for individuals born since 1925, with the youngest age groups experiencing the steepest decline in mortality rate at 25.9 percent per decade, and the oldest age groups experiencing a 6.8 percent per decade decline. Dr. Eric Kort, the lead author of this study, claims that public reports often focus on cancer incidence rates and underappreciate the progress that has been achieved in reduced cancer mortality rates.

The effectiveness and expansion of available therapies has seen significant improvements since the 1970s. For example, lumpectomy replaced more invasive mastectomy surgery for the treatment of breast cancer. Treatment of childhood leukemia and chronic myeloid leukemia (CML) have undergone major advances since the war on cancer began. The drug Gleevec now cures most CML patients, compared to previous therapy with interferon, which extended life for approximately 1 year in only 20-30 percent of patients.

Dr. Steven Rosenberg, chief of surgery at the NCI has said that as of the year 2000, 50% of all diagnosed cases of cancer are curable through a combination of surgery, radiation, and chemotherapy. Cancer surveillance experts have reported a 15.8 percent decrease in the age-standardized death rate from all cancers combined between 1991 and 2006 along with an approximately 1 percent annual decrease in the rate of new diagnoses between 1999 and 2006. A large portion of this decreased mortality for men was attributable to smoking cessation efforts in the United States.

A 2010 report from the American Cancer Society found that death rates for all cancers combined decreased 1.3% per year from 2001 to 2006 in males and 0.5% per year from 1998 to 2006 in females, largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colorectum) and 2 major cancer sites in women (breast and colorectum). Cancer death rates between 1990 and 2006 for all races combined decreased by 21.0% among men and by 12.3% among women. This reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. Despite these reductions, the report noted, cancer still accounts for more deaths than heart disease in persons younger than 85 years.

An improvement in the number of cancer survivors living in the U.S. was indicated in a 2011 report by the CDC and the NCI, which noted that the number of cancer survivors in 2007 (11.7 million) increased by 19% from 2001 (9.8 million survivors). The number of cancer survivors in 1971 was 3 million. Breast, prostate, and colorectal cancers were the most common types of cancer among survivors, accounting for 51% of diagnoses. As of January 1, 2007, an estimated 64.8% of cancer survivors had lived ≥5 years after their diagnosis of cancer, and 59.5% of survivors were aged ≥65 years. A continued decline in cancer rates in the U.S. among both women and men, across most major racial groups, and in the most common cancer sites (lung, colon and rectum), was indicated in a 2013 report by the National Cancer Institute. However, the same report indicated an increase from 2000 to 2009 in cancers of the liver, pancreas and uterus.

Challenges

A multitude of factors have been cited as impeding progress in finding a cure for cancer and key areas have been identified and suggested as important to accelerate progress in cancer research. Since there are many different forms of cancer with distinct causes, each form requires different treatment approaches. However, this research could still lead to therapies and cures for many forms of cancer. Some of the factors that have posed challenges for the development of preventive measures and anti-cancer drugs and therapies include the following:

  • Inherent biological complexity of the disease:
  • Roadblocks to translational medicine
  • Challenges of early detection and diagnosis
  • The drug approval process
  • Availability of and access to patients with suitable tumor tissue for research
  • Challenges in implementing preventive measures, such as the development and use of preventive drugs and therapies
  • Choropleth mapping of the changes over time, of the national incidence rate, by cancer type, relative to the population at risk, is a technical challenge.

“The public is so jaded by cancer research media attention at the moment... And let's face it, rather embarrassingly, most claimed ‘breakthroughs’ are not proving to significantly advance cancer therapies... It is a real conundrum for researchers today, because ‘early publicity’ is needed for funding, capital raising and professional kudos, but not too helpful for the public who then think that an immediate cure might be just around the corner.” Professor Brendon Coventry, 9 July 2013

Modern cancer research

Genome-based cancer research projects

The rise of a new class of molecular technologies developed during the Human Genome Project opens up new ways to study cancer and holds the promise for the discovery of new aspects of cancer biology that could eventually lead to novel, more effective diagnostics and therapies for cancer patients. These new technologies are capable of screening many biomolecules and genetic variations such as SNPs and copy number variations in a single experiment and are employed within functional genomics and personalized medicine studies.

Speaking on the occasion of the announcement of $1 billion in new funding for genome-based cancer research, Dr. Francis Collins, director of the NIH claimed, "We are about to see a quantum leap in our understanding of cancer." Harold Varmus, after his appointment to be the director of the NCI, said we are in a "golden era for cancer research," poised to profit from advances in our understanding of the cancer genome.

High-throughput DNA sequencing has been used to study the whole genome sequence of two different cancer tissues: a small-cell lung cancer metastasis and a malignant melanoma cell line. The sequence information provides a comprehensive catalog of approximately 90% of the somatic mutations in the cancerous tissue, providing a more detailed molecular and genetic understanding of cancer biology than was previously possible, and offering hope for the development of new therapeutic strategies gleaned from these insights.

The Cancer Genome Atlas

The Cancer Genome Atlas (TCGA), a collaborative effort between the National Cancer Institute and the National Human Genome Research Institute, is an example of a basic research project that is employing some of these new molecular approaches. One TCGA publication notes the following:

Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas...Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

In a cancer research funding announcement made by President Obama in September 2009, TCGA project is slated to receive $175 million in funding to collect comprehensive gene sequence data on 20,000 tissue samples from people with more than 20 different types of cancer, in order to help researchers understand the genetic changes underlying cancer. New, targeted therapeutic approaches are expected to arise from the insights resulting from such studies.

Cancer Genome Project

The Cancer Genome Project at the Wellcome Trust Sanger Institute aims to identify sequence variants/mutations critical in the development of human cancers. The Cancer Genome Project combines knowledge of the human genome sequence with high throughput mutation detection techniques.

Cancer research supportive infrastructure

Advances in information technology supporting cancer research, such as the NCI's caBIG project, promise to improve data sharing among cancer researchers and accelerate "the discovery of new approaches for the detection, diagnosis, treatment, and prevention of cancer, ultimately improving patient outcomes."

Modern cancer treatment

Cancer clinical trials

Researchers are considering ways to improve the efficiency, cost-effectiveness, and overall success rate of cancer clinical trials.

Increased participation in rigorously designed clinical trials would increase the pace of research. Currently, about 3% of people with cancer participate in clinical trials; more than half of them are patients for whom no other options are left, patients who are participating in "exploratory" trials designed to burnish the researchers' résumés or promote a drug rather than to produce meaningful information, or in trials that will not enroll enough patients to produce a statistically significant result.

Targeted tumor treatment

A major challenge in cancer treatment is to find better ways to specifically target tumors with drugs and chemotherapeutic agents in order to provide a more effective, localized dose and to minimize exposure of healthy tissue in other parts of the body to the potentially adverse effects of the treatments. The accessibility of different tissues and organs to anti-tumor drugs contributes to this challenge. For example, the blood–brain barrier blocks many drugs that may otherwise be effective against brain tumors. In November 2009, a new, experimental therapeutic approach for treating glioblastoma was published in which the anti-tumor drug Avastin was delivered to the tumor site within the brain through the use of microcatheters, along with mannitol to temporarily open the blood–brain barrier permitting delivery of the chemotherapy into the brain.

Public education and support

An important aspect to the war on cancer is improving public access to educational and supportive resources, to provide individuals with the latest information about cancer prevention and treatment, as well as access to support communities. Resources have been created by governmental and other organizations to provide support for cancer patients, their families and caregivers, to help them share information and find advice to guide decision making.

 

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Cancer research

From Wikipedia, the free encyclopedia

Sidney Farber is regarded as the father of modern chemotherapy.

Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure.

Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and compare applications of the various cancer treatments. These applications include surgery, radiation therapy, chemotherapy, hormone therapy, immunotherapy and combined treatment modalities such as chemo-radiotherapy. Starting in the mid-1990s, the emphasis in clinical cancer research shifted towards therapies derived from biotechnology research, such as cancer immunotherapy and gene therapy.

Cancer research is done in academia, research institutes, and corporate environments, and is largely government funded.

History

Cancer research has been ongoing for centuries. Early research focused on the causes of cancer. Percivall Pott identified the first environmental trigger (chimney soot) for cancer in 1775 and cigarette smoking was identified as a cause of lung cancer in 1950. Early cancer treatment focused on improving surgical techniques for removing tumors. Radiation therapy took hold in the 1900s. Chemotherapeutics were developed and refined throughout the 20th century.

The U.S. declared a "War on Cancer" in the 1970s, and increased the funding and support for cancer research.

Seminal papers

Some of the most highly cited and most influential research reports include:

Types of research

Cancer research encompasses a variety of types and interdisciplinary areas of research. Scientists involved in cancer research may be trained in areas such as chemistry, biochemistry, molecular biology, physiology, medical physics, epidemiology, and biomedical engineering. Research performed on a foundational level is referred to as basic research and is intended to clarify scientific principles and mechanisms. Translational research aims to elucidate mechanisms of cancer development and progression and transform basic scientific findings into concepts that can be applicable to the treatment and prevention of cancer. Clinical research is devoted to the development of pharmaceuticals, surgical procedures, and medical technologies for the eventual treatment of patients.

Prevention and epidemiology

Cause and development of cancer

Numerous cell signaling pathways are disrupted in the development of cancer.

Research into the cause of cancer involves many different disciplines including genetics, diet, environmental factors (i.e. chemical carcinogens). In regard to investigation of causes and potential targets for therapy, the route used starts with data obtained from clinical observations, enters basic research, and, once convincing and independently confirmed results are obtained, proceeds with clinical research, involving appropriately designed trials on consenting human subjects, with the aim to test safety and efficiency of the therapeutic intervention method. An important part of basic research is characterization of the potential mechanisms of carcinogenesis, in regard to the types of genetic and epigenetic changes that are associated with cancer development. The mouse is often used as a mammalian model for manipulation of the function of genes that play a role in tumor formation, while basic aspects of tumor initiation, such as mutagenesis, are assayed on cultures of bacteria and mammalian cells.

Genes involved in cancer

Main article: Oncogenomics
See also: Databases for oncogenomic research

The goal of oncogenomics is to identify new oncogenes or tumor suppressor genes that may provide new insights into cancer diagnosis, predicting clinical outcome of cancers, and new targets for cancer therapies. As the Cancer Genome Project stated in a 2004 review article, "a central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis (cancer genes)." The Cancer Genome Atlas project is a related effort investigating the genomic changes associated with cancer, while the COSMIC cancer database documents acquired genetic mutations from hundreds of thousands of human cancer samples.

These large scale projects, involving about 350 different types of cancer, have identified ~130,000 mutations in ~3000 genes that have been mutated in the tumours. The majority occurred in 319 genes, of which 286 were tumour suppressor genes and 33 oncogenes.

Several hereditary factors can increase the chance of cancer-causing mutations, including the activation of oncogenes or the inhibition of tumor suppressor genes. The functions of various onco- and tumor suppressor genes can be disrupted at different stages of tumor progression. Mutations in such genes can be used to classify the malignancy of a tumor.

In later stages, tumors can develop a resistance to cancer treatment. The identification of oncogenes and tumor suppressor genes is important to understand tumor progression and treatment success. The role of a given gene in cancer progression may vary tremendously, depending on the stage and type of cancer involved.

Detection

Prompt detection of cancer is important, since it is usually more difficult to treat in later stages. Accurate detection of cancer is also important because false positives can cause harm from unnecessary medical procedures. Some screening protocols are currently not accurate (such as prostate-specific antigen testing). Others such as a colonoscopy or mammogram are unpleasant and as a result some patients may opt out. Active research is underway to address all these problems.

Treatment

Main article: Treatment of cancer

Emerging topics of cancer treatment research include:

Research funding

Cancer research is funded by government grants, charitable foundations and pharmaceutical and biotechnology companies.

In the early 2000s, most funding for cancer research came from taxpayers and charities, rather than from corporations. In the US, less than 30% of all cancer research was funded by commercial researchers such as pharmaceutical companies. Per capita, public spending on cancer research by taxpayers and charities in the US was five times as much in 2002–03 as public spending by taxpayers and charities in the 15 countries that were full members of the European Union. As a percentage of GDP, the non-commercial funding of cancer research in the US was four times the amount dedicated to cancer research in Europe. Half of Europe's non-commercial cancer research is funded by charitable organizations.

The National Cancer Institute is the major funding institution in the United States. In the 2016 fiscal year, the NCI funded $5.2 billion in cancer research.

Difficulties

Difficulties inherent to cancer research are shared with many types of biomedical research.

Cancer research processes have been criticised. These include, especially in the US, for the financial resources and positions required to conduct research. Other consequences of competition for research resources appear to be a substantial number of research publications whose results cannot be replicated.

Public participation

One can share computer time for distributed cancer research projects like Help Conquer Cancer. World Community Grid also had a project called Help Defeat Cancer. Other related projects include the Folding@home and Rosetta@home projects, which focus on groundbreaking protein folding and protein structure prediction research.

Members of the public can also join clinical trials as healthy control subjects or for methods of cancer detection.

Dominance of cancer research

MD Anderson Cancer Center is ranked as one of the top cancer research institutions.

Cancer research has grown considerably as indicated by the number of records that have been indexed in the MEDLINE database, in the 1950s the proportion of cancer-related entries was approximately 6% of all entries and this has risen to 16% in 2016. This rise may be attributed to the impact of scientific advances such as genomics, computing and mathematics, which have had a stronger influence in cancer than in other areas such as cardiovascular conditions.

Organizations

Breast cancer awareness ribbon statue in Kentucky

Organizations exist as associations for scientists participating in cancer research, such as the American Association for Cancer Research and American Society of Clinical Oncology, and as foundations for public awareness or raising funds for cancer research, such as Relay For Life and the American Cancer Society.

Awareness campaigns

Supporters of different types of cancer have adopted different colored awareness ribbons and promote months of the year as being dedicated to the support of specific types of cancer. The American Cancer Society began promoting October as Breast Cancer Awareness Month in the United States in the 1980s. Pink products are sold to both generate awareness and raise money to be donated for research purposes. This has led to pinkwashing, or the selling of ordinary products turned pink as a promotion for the company.
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Limbic encephalitis

From Wikipedia, the free encyclopedia

Limbic encephalitis is a form of encephalitis, a disease characterized by inflammation of the brain. Limbic encephalitis is caused by autoimmunity: an abnormal state where the body produces antibodies against itself. Some cases are associated with cancer and some are not. Although the disease is known as "limbic" encephalitis, it is seldom limited to the limbic system and post-mortem studies usually show involvement of other parts of the brain. The disease was first described by Brierley and others in 1960 as a series of three cases. The link to cancer was first noted in 1968 and confirmed by later investigators.

The majority of cases of limbic encephalitis are associated with a tumor (diagnosed or undiagnosed). In cases caused by tumor, recovery can only occur following complete removal of the tumor, which is not always possible. Limbic encephalitis is classified according to the auto-antibody that causes the disease. The most common types are:

Since 1999, following the publication of a case report of a 15-year-old teenager of Indian descent from South Africa who developed subacute memory loss subsequent to herpes simplex type 1 encephalitis, similar cases of non-paraneoplastic LE have been described, as has its association with auto-antibodies and response to steroid. Limbic encephalitis associated with voltage-gated potassium channel antibodies (VGKC-Abs) may frequently be non-paraneoplastic. A recent study of 15 cases of limbic encephalitis found raised VGKC-Abs associated with non-paraneoplastic disorders and remission following immunosuppressive treatment.

Classification

Limbic encephalitis is broadly grouped into two types: paraneoplastic limbic encephalitis and non-paraneoplastic limbic encephalitis.

  • Paraneoplastic limbic encephalitis (PNLE) is caused by cancer or tumor, and may be treated by removal of the tumor.
  • Non-paraneoplastic limbic encephalitis (NPLE) is not associated with cancer. More common than PNLE, it is caused by an infection, auto-immune disorder, or other condition that may never be identified.

Symptoms and signs

Symptoms develop over days or weeks. The subacute development of short-term memory deficits is considered the hallmark of this disease, but this symptom is often overlooked, because it is overshadowed by other more obvious symptoms such as headache, irritability, sleep disturbance, delusions, hallucinations, agitation, seizures and psychosis, or because the other symptoms mean the patient has to be sedated, and it is not possible to test memory in a sedated patient.

Cause

Limbic encephalitis is associated with an autoimmune reaction. In non-paraneoplastic limbic encephalitis, this is typically due to infection (commonly herpes simplex virus) or as a systemic autoimmune disorder. Limbic encephalitis associated with cancer or tumors is called paraneoplastic limbic encephalitis.

Diagnosis

The diagnosis of limbic encephalitis is extremely difficult and it is usual for the diagnosis to be delayed for weeks. The key diagnostic test (detection of specific auto-antibodies in cerebrospinal fluid) is not routinely offered by most immunology laboratories. Some of the rarer auto-antibodies (e.g., NMDAR) have no commercially available assay and can only be measured by a very small number of research laboratories worldwide, further delaying diagnosis by weeks or months. Most patients with limbic encephalitis are initially diagnosed with herpes simplex encephalitis, because the two syndromes cannot be distinguished clinically. HHV-6 (human herpes virus 6) encephalitis is also clinically indistinguishable from limbic encephalitis.

There are two sets of diagnostic criteria used. The oldest are those proposed by Gultekin et al. in 2000.

A revised set of criteria were proposed by Graus and Saiz in 2005.

The main distinction between the two sets of criteria is whether or not the detection of a paraneoplastic antibody is needed for diagnosis.

Antibodies against intracellular neuronal antigens

The main antibodies within this group are those against Hu, Ma2, CV2, amphiphysin and Ri. The syndrome of anti-Ma2 encephalitis may be clinically mistaken for Whipple's disease.

Antibodies against cell membrane antigens

The main antibodies within this group are those against N-methyl-D-aspartate receptors (NMDAR) and the voltage-gated potassium channel-complex (VGKC-complex). Anti-NMDAR encephalitis is strongly associated with benign tumours of the ovary (usually teratomata or dermoid cysts). Anti-VGKC-complex encephalitis is most often not associated with tumours.

Patients with NMDAR encephalitis are frequently young women who present with fever, headache and fatigue. This is often misdiagnosed as influenza, but progresses to severe behavioural and personality disturbance, delusions, paranoia and hallucinations. Patients may therefore initially be admitted to a psychiatric ward for acute psychosis or schizophrenia. The disease then progresses to catatonia, seizures and loss of consciousness. The next stage is hypoventilation (inadequate breathing) requiring intubation, orofacial dyskinesia and autonomic instability (dramatic fluctuations in blood pressure, temperature and heart rate).

Investigation

Cerebrospinal fluid (CSF)

Examination of cerebrospinal fluid (CSF) shows elevated numbers of lymphocytes (but usually < 100 cells/μl); elevated CSF protein (but usually <1.5 g/l), normal glucose, elevated IgG index and oligoclonal bands. Patients with antibodies to voltage-gated potassium channels may have a completely normal CSF examination.

Neuroimaging

Brain MRI is the mainstay of initial investigation pointing to limbic lobe pathology revealing increased T2 signal involving one or both temporal lobes in most cases.

Serial MRI in LE starts as an acute disease with uni- or bilateral swollen temporomesial structures that are hyperintense on fluid attenuation inversion recovery and T2-weighted sequences. Swelling and hyperintensity may persist over months to years, but in most cases progressive temporomesial atrophy develops.

PET-CT is not an essential investigation but can help in suspected cases with MRI negative for early diagnosis.

Neuro-electrophysiology

EEG is mostly nonspecific slowing and epileptiform activity arising from temporal lobes.

Treatment

Limbic encephalitis is a rare condition with no randomised-controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide and rituximab.

If an associated tumour is found, then recovery is not possible until the tumour is removed. Unfortunately, this is not always possible, especially if the tumour is malignant and advanced.

History

Limbic encephalitis
Brain limbicsystem.svg
The limbic system within the brain.












 

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