News from the AACR meeting 2013 in Washington, DC


The AACR 2013 Meeting in Washington DC

AACR Meeting 2013

To find out about AACR you can click on this link:   http://www.aacr.org/home/about-us.aspx

News from the AACR 2013 Meeting

The AACR publishes progress reports on the development of cancer occurrences and advancements made in the fight of cancer.

If interested, you can access the  2012 report called

“AACR Cancer Progress Report 2012. Making Research Count for Patients:

A new Day”

at http://cancerprogressreport.org/Pages/default.aspx

— . —

What have we learned from the AACR meeting?

There were over 5,500 posters presented and I found it impossible to review and read all of them in the period of three and a half days I was attending the meeting. Therefore I can only focus on some highlights of the meeting that jumped to my attention. I am biased based on my interest in subjects, methods and technologies presented.

Here are a few:

  • Cancer Prevention
  • Stabled peptides as next-generation therapeutics. You may also want to read my earlier post on this subject.
  • Non-coding RNAs in Cancer: From pathogenesis to therapeutics.
  • Antibody Drug Conjugates
  • Inflammation and Cancer
  • Epigenetics of Cancer
  • Epigenetic Targets for Cancer Therpeutics
  • Next-Generation Sequencing and Analysis of Genomes.
  • Cancer Stem Cells: biologic and clinical implications.
  • GWAS:  The next steps.  [GWAS stands for Genome-wide association studies]
  • Techniques for Assessing Circulating Tumor Cells, Circulating DNA, and microRNAs.
  • Therapeutic Nanotechnology.
  • Translational Control of Cancer
  • DNA Damage Response
  • Telomers in Cancer

And there were many, many, many more to review as well.

And, the 85th birthday of Nobel Laureate Dr. James D. Watson was celebrated on Saturday afternoon April 06, 2013.

!!!  Happy Birthday Dr. Watson  !!!

— . —

What is cancer and why we all should support cancer research?

Everybody is at risk to get cancer independent of age, gender, race, ethnicity, socioeconomic status or political affiliation. In the USA alone one out of every three women and one out of every two man will be diagnosed with having cancer in their lifetimes. Sadly, despite progress made in the diagnosis and treatment of cancer, the grim reality that too many people are losing the battle against this disease remains.

It is estimated that more than 1.64 million Americans will have been diagnosed in 2012 and more than 570,000 will succumb to the disease.

Presently support for cancer research in the USA is waning. This should not be the case. Research performed in the recent decade has shown that cancer research saves lives, fuels the development of new and better ways to prevent, detect, diagnose and treat cancer in all age groups. Since an increasing proportion of the population is over the age of 65 it is predicted that cancer will soon become the number one killer of Americans, a trend expected to occur globally.

Due to the dedicated work of thousands of cancer and biomedical researchers the world over we now know that cancer is not a single disease, but 200 or more different diseases. Even though the diverse nature of cancer is overwhelming we have discovered that some common biological processes are involved in cancer. For example, changes in an individual’s genes alter specific components of the molecular machinery of a cell that drives cancer initiation, development and spread, and that therapies specifically targeting these defects are often beneficial to the patients while having less toxic side effects than older therapies. Biomedical researchers and clinicians are now better positioned than ever to develop and use more effective interventions to save more lives from cancer. Unfortunately, to do so will require the commitment of our society to invest more resources into productive biomedical research enterprises.

It has become apparent in recent years that one of the key areas that promises increased progress is cancer prevention. As a direct result of our scientific understanding of the timing, sequence and frequency of changes on the molecular level underlying cancer development and spreading throughout the body, we now know that there are point of intervention than can be greatly exploited in order to stop certain cancers in their tracks. The goal is to devise and to develop therapies that inhibit the cancers form further development before they do further damage. The AACR Cancer Progress Report 2012 shows that advances in cancer prevention and early detection have resulted in some of the greatest reductions in cancer mortality in recent decades. The implementation of public health measures to reduce exposure to cancer-causing agents, intervening medically to treat or prevent infectious causes of cancer and the introduction of population-based screening practice have contributed to this progress.

It is estimated that about two out of every three (ca. 60%) deaths in the US in 2012 will be due to preventable causes such as tobacco abuse, obesity, physical inactivity and failure to use or comply with interventions that treat or prevent infectious causes of cancer. All these facts underscore the need for continued support of cancer research as well as finding ways and avenues on how to inform the public effectively to encourage and help people to change their behavior before the onset of the initiation and development of cancer. The following table lists the ten most frequent occurring cancers in the US.

— . —

The ten Most Frequent Cancer in the United Startes

Cancer site Cases per year Deaths per year
Breast 184,200 (15.1%) 41,200 (7.5%)
Prostate 180,400 (14.8%) 31,900 (5.8%)
Lung 164,100 (13.4%) 156,900 (28.4%)
Colon/rectum 130,200 (10.7%) 56,300 (10.2%)
Lymphomas 62,300 (5.1%) 27,500 (5.0%)
Bladder 53,200 (4.4%) 12,200 (2.2%)
Uterus 48,900 (4.0%) 11,100 (2.0%)
Skin (melanoma) 47,700 (3.9%) 7,700 (1.4%)
Kidney 31,200 (2.6%) 11,900 (2.2%)
Leukemias 30,800 (2.5%) 12,100 (2.2%)
Subtotal 933,000 (76.5%) 368,800 (66.8%)
All sites 1,220,100 (100%) 552,200 (100%)

Source: American Cancer Society, Cancer Facts and Figures—2000 in  http://www.ncbi.nlm.nih.gov/books/NBK9963/.

— . —

How does cancer develop?

The Development and Causes of Cancer

Small genetic changes in the somatic genome lead to cancer. Many mutations are necessary for a cell to become a cancer cell.  One change does not lead to cancer right away. Normally many changes are needed to cause cancer. These changes can accumulate over time increasing the risk to get cancer as we age.  Colorectal cancer is the best understood cancer. In the US on average 60,000 deaths are caused by this cancer per year and approximately 135,000 new cases are diagnosed each year. Colorectal cancer develops over a series of steps. An initial genetic change can lead to a change in the tissue. This can lead to the formation of a small polyp in the lining of the colon however cell division in the polyp’s tissue is increased. Over time, further genetic alterations in a cell within the polyp can lead to a more advanced precancerous lesion. Over time, if more additional genetic mutations are acquired a stage of dysplasia, referring to the abnormality of development of a cell, is reached  leading to a change in cell shape. As the genetic changes accumulate causing further cellular changes precancerous lesion may evolve into cancerous lesions within the tissue. Ultimately, as more and more mutations accumulate the cancer cells can gain the ability to metastasize allowing the mutated cells to invade nearby blood and lymphatic vessels.  Mutated p53 tumor suppressor gene and a ras oncogene are frequently seen in colorectal cancer. To allow cancer to occur at least one oncogene and the loss of numerous tumor suppressor genes must happen. Since loss of function of the tumor suppressor is a recessive trait both alleles of the tumor suppressor must be mutated. Further, gene mutations can influence the type of drugs used in cancer treatment. If colon cancer tumors have the KRAS gene mutation the cancer cells do not respond to certain drug treatments that block EGF receptor signaling. Knowing this will allow doctors to select the correct drugs that will kill the tumor cells.

Events and steps leading to the development of cancer are illustrated below.

Cancer steps 1  Cancer steps 2  Cancer steps 3 Cancer development 2

Several steps are needed for a cancer to develop:

  • Initiation = DNA damaged
  • Promotion = mutated cell is stimulated to grow faster
  • Progression = wildly mutated cells mutate even more, dividing rapidly, tumor
  • Conversion = metastasis occurs

Normal tissue can be viewed as a mosaic of cells in which different X chromosomes (X1 and X2) have been inactivated.  Since tumors develop from a single initially altered cell each tumor cell displays the same pattern of X inactivation (X1 inactive, X2 active). Next, the development of a cancer is initiated when a single mutated cell begins to proliferate abnormally. If following additional mutations select for more rapidly growing cells within the population the result is progression of the tumor by increasingly rapid growth and malignancy. A single initially altered cell can give rise to a proliferative cell population, which progresses first to benign adenomas of increasing size and then to malignant carcinoma. Ultimately, the cancer cells invade the underlying connective tissue and penetrates blood and lymphatic vessels allowing the cancer to spread throughout the body [Source: The Development and Causes of Cancer].

IMG_4189 IMG_4187 IMG_4188

A happy normal cell mutates into a unhappy cancer cell.

— . —

Origin of the term cancer

The Greek physician Hippocrates (460-370 BC) considered as the “Father of Medicine” has used the terms carcinos and carcinoma to describe non-ulcer forming and ulcer-forming tumors in ancient times. These words refer to a crab in the Greek language. It is thought that these terms were most likely applied to the disease because the finger-like spreading projections from a cancer looked like the shape of a crab. Celsus (28-50 BC) a Roman physician later translated the Greek term into cancer, the Latin word for crab. Galen (130-200 AD) later used the word oncos (Greek for swelling) to describe tumors. Galen’s term, who was also a Roman physician, is now used as a part of the name for cancer specialists — oncologists.”

Cancer is not just one disease and there are more than 100 different types of cancer. The name for a cancer originates from the organ or type of cell in which it starts. For example, cancer starting in the colon is called colon cancer.

Cancer types include:

  • Carcinoma: This cancer begins in the skin or in tissues that line or cover internal organs. Subtypes include adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma.
  • Sarcoma: This cancer begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
  • Leukemia: This cancer begins in blood-forming tissue such as the bone marrow. It causes large numbers of abnormal blood cells to be produced and enter the blood.
  • Lymphoma and myeloma: This cancers begins in the cells of the immune system.
  • Central nervous system cancers:  This cancers begins in the tissues of the brain and spinal cord.

For more info and definitions other cancer-related terms, see NCI’s Dictionary of Cancer Terms and the A to Z List of Cancers or the list of Cancers by Body Location/System.

Cancer Prevention

Research suggests that more than 50% of all cancers occurring today are preventable by applying knowledge we have already gained. Tobacco, obesity, and physical inactivity are causes of cancer that can be modified. The application of sound scientific knowledge and ones individual and/or social commitment to change will hopefully decrease the cancer causing burden and help to decrease the risk for getting cancer in the future. Scientific data suggests that an estimated 54.5% of all cancer cases may be preventable and there are research-proven strategies and interventions available that can prevent either a substantial proportion of cancer or a reoccurence after diagnosis and successful treatment.

For example, behavioral changes and interventions early in the lives of young women can reduce the risk for breast and cervical cancer. This is because these cancers develop over years and decades. Vaccination for viruses, physical activity, and avoiding extensive sun exposure has been shown to be most effective when begun early in life. This is true for both, young men and for young women.

Furthermore, minimizing the risk of infections caused by viruses and bacteria also decreases the risk for cancer. Infections with the human papillomavirus (HPV; cervix cancer), Helicobacter pylori (stomach cancer), and hepatitis B and C (liver cancer) together account for approximately 18% of all cancers globally.  It is estimated that HPV vaccination early in life can reduce the incidence of cervical cancer by 50 to 70%.

In addition, our life-style habits influence our cancer risk. How we live, what we eat, how we exercise, which drugs, medications and supplements we take will influence our risk of developing tumors or cancer. Choosing the right nutrition starting early in live may actually help prevent close or more than 50% of all cancers. Lifestyle factors, including our diet, can make a huge difference in helping us to fight off cancer. Some foods, especially ones that contain large amounts of lard, are known to increase the risk of cancer. Other foods support the health of the human body and strengthen the immune system as well. Making smart food choices can protect our health, make us feel better, and boost our ability to fight off cancer and other disease.

Causes of cancer and potential reduction in cancer burden through preventive measures

Cause % cancer caused Deaths in United States (ACS) Possible reduction (%) Period of time (years) Evidence example
Smoking 33 188,744 75 10–20 Comparison of lung cancer mortality by state
Overweight and obesity 20 114,390 50 2–20 Bariatric surgery and sustained changes in weight and markers
Diet 5 28,600 50 5–20 Folate and colorectal cancer
Lack of exercise 5 28,600 85 5–20 Adolescent physical activity
Occupation 5 28,600 50 20–40 Asbestos workplace regulation
Viruses 5 28,600 100 20–40 Liver cancer reduction by vaccine
Family history 5 28,600 50 2–10 Bilateral oophorectomy for BRCA1/2.Aspirin trial for Lynch syndrome.
Alcohol 3 17,200 50 5–20 Regulation
UV and ionizing radiation 2 11,400 50 5–40 Reduced medical exposures
Prescription drugs 1 5,720 50 2–10 Hormone therapy–related drop in breastcancer
Reproductive factors 3 17,200 0 N/A N/A
Pollution 2 11,400 0 N/A N/A

N/A, not applicable. Adapted from Graham A. Colditz, Kathleen Y. Wolin, and Sarah Gehlert; Applying What We Know to Accelerate Cancer Prevention. Sci Transl Med. 2012 March 28; 4(127): 127rv4. doi:10.1126/scitranslmed.3003218.

Medical interventions proven to prevent cancer

RCT, randomized controlled trial.

Intervention Target Magnitude of reduction Period of time (years) Evidence
Aspirin Total cancer mortality 20% 20 Follow-up of eight randomized cancer trials (RCTs).
Aspirin Colon cancer mortality 40% 20 Five RCTs and RCTs iIn Lynch syndrome.
SERMs (tamoxifen, raloxifene) Breast cancer incidence 40–50% 5+ RCTs
Salpingo-oophorectomy Familial breast cancer 50% 3+ Synthesis of observational data.
Screening for colon cancer (sigmoidoscopy and colonoscopy) Colon cancer mortality Sigmoidoscopy,30–40%Colonoscopy, 50% 10 UK RCT sigmoidoscopy.Observational data and disease modeling
Vaccines (HPV and hepatitis) Cervical cancer incidence 50–100% 20+ Modeling vaccination rates and persistence ofProtection.
Vaccines (HPV and hepatitis) Liver cancer incidence 70–100% 20+ Observational follow-up data from universal population vaccination program at birth.
Mammography Breast cancer mortality 30% 10–20 RCT and modeling.
Spiral computed tomography for lung cancer  Lung cancer mortality 20% 6+ RCT

Note 1: The removal of an ovary together with the fallopian tube is called salpingo-oophorectomy or unilateral salpingo-oophorectomy (USO). Removing both ovaries and both fallopian tubes is called bilateral salpingo-oophorectomy (BSO).

Note 2:  SERMs or Selective Estrogen Receptor Modulators are compounds that selectively inhibit or stimulate estrogen-like action in various tissues. Phytoserms are SERMs from a botanical source.

— . —

The Long and Difficult Road to a Clinically Useful Drug

The development of a drug that is clinically useful is a long and winding road. Ultimately phase III during clinical trials will determine if the drug is useful and will make it to market. This is illustrated in the next figures.

Drug Development 1

Drug Development 2

Source:  AACR Cancer Progress Report 2012.

— . —

New Drugs for Cancer Treatment

Newly FDA-Approved Drugs and Indications for the Treatment of Cancer and Precancerous Lesions 

September 2011 to August 2012

Angiogenesis Inhibitors

Approved Indication Generic Name Structure Trade Name
Kidney cancer   Axitinib Kinase Inhibitor Drug   Axitinib Inlyta
Soft tissue sarcomas (New indication) PazopanibReceptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth and inhibits angiogenesis.  Pazopanib Votrient
Colorectal cancer  ziv-afliberceptFusion proteinAngiogenesis inhibitor Aflibercept Zaltrap

Cell Cytoskeleton Modifying Agents

Approved Indication Generic Name Structure Trade Name
Certain leukemias and lymphomas Vincristine sulfate liposomesVincristine binds to tubulin dimers, inhibiting assembly of microtubule structures.  Vincristine Marqibo

Cell Signaling Inhibitors

Approved Indication Generic Name Structure Trade Name
Non-cancerous kidney(New indication)

HER2+ breast cancers

EverolimusInhibitor of mammalian target of rapamycin (mTOR).  Everolimus Afinitor
HER2+ breast cancers PertuzumabMonoclonal Antibody

Binds to HER2 and inhibits the dimerization of HER2 with other HER receptors

Pertuzumab Perjeta
Myelofibrosis RuxolitinibJanus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.  Ruxolitinib Jakafi
Certain type of skin cancer VismodegibActs as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway  Vismodegib Erivedge

Hormone/Antihormone

Approved Indication Generic Name Structure Trade Name
Prostate cancer EnzalutamideAndrogen receptor antagonist  Enzalutamide Xtandi

Immune System Modifiers

Approved Indication Generic Name Structure Trade Name
Precancerous skin lesions Ingenol mebutateInducer of cell death  Ingenol mebutate Picato

Proteosome Inhibitor

Approved Indication Generic Name Structure Trade Name
Multiple myeloma BortezomibProteasome inhibitor  Bortexomib Velcade
Multiple myeloma CarfilzomibSelective proteasome inhibitor  Caefilzomib Kyprolis

And there are 15 Breast Cancer Drugs in the Pipeline Right Now



Categories: Antibodies, Antigens, Bioanalysis, Cancer, cell culture, Cell lines, Centromere, Chromatin, DNA, DNA damage, Epigenetics, Food, Genetics, Genotyping, Human Genetics, Leukemia, Melanoma, non-coding RNAs, Peptide Mimics, Peptide Synthesis, peptides, Scientific meetings, Stapled Peptides, Synthesis, Telomere, Vaccines

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