Reported by: Dr. Venkat S. Karra, Ph.D.
Cancer remains the second leading cause of death by disease. Hundreds of new medicines to treat cancer are now being developed for lessening the burden of cancer to patients, their families and society.
Biopharmaceutical researchers are now working on 981 medicines for cancer. Many are high-tech weapons to fight the disease, while some involve innovative research into using existing medicines in new ways, the report says.
Recent developments in early detection and a steady stream of new and improved treatments suggesting that cancer is a manageable chronic disease (not a deadly one any more). Families and patients alike are with increasing expectations from the industry for more and better treatment options and America’s biopharmaceutical research companies are responding to that.
America’s biopharmaceutical research companies are working on many new cutting-edge approaches to fight cancer. They include:
• A medicine that interferes with the metabolism of cancer cells by depriving them of the energy provided by glucose.
• A medicine for acute myeloid leukemia (AML) that inhibits cancer cells with a mutation found in about a third of AML sufferers.
• A therapy that uses nanotechnology to target the delivery of medicines to cancer cells, potentially overcoming some limitations of existing treatments.
http://www.phrma.org/sites/default/files/1000/phrmamedicinesindevelopmentcancer2012.pdf
A medicine that interferes with the metabolism of cancer cells by depriving them of the energy provided by glucose.
I’m not sure that this idea is likely to bear fruit. I say this because glucose is essential for life, whether it is derived from proteolysis and gluconeogenesis, short term from liver glycogenolysis (not muscle). The highest yield for energy is from lipid catabolism stressing the importance of the high energy ~ PO4 bond and acetyl coenzyme A. Depriving them of the energy provided by glucose is not adaptive.
Why is this? This is because a fundamental problem is impaired respiration through entry into the Krebs cycle by conversion of axaloacetate to malate, which becomes a stumbling block, and is tied to gluconeogenesis driven lactate production as a major source of energy.
Well, you may say. That is unimaginable. The associated problem is proteolysis and sarcopenia, driven by an accompanied “inflammatory” state related at the base to TLR receptor, signaling pathways, and genome-expression and metabolomic events that have to be selectively identified in order to differentially attack specific neoplastic conditions without harming the metabolically “safe” cells.
The report from which this is a source has an unexpected observation:
“about one-third of the cancer deaths expected this year will be related to overweight or obesity, physical inactivity, and poor nutrition”. This is interesting, if not so easy to believe because of the so called “epidemic of obesity”, which gives us an epidemiological correlation, but not an explanation.
Conceding that it has merit, then what do we make of this.
The obesity can probably weigh in as a pro-inflammatory condition that leads to type 2 diabetes. This can be modified by decrease in both portion size, and of beef. There are two concerns with moderation in red meat. The first is the amount of n-6 omega fatty acids. The second is perhaps a not fully substantiated virus genome transmission. Poor nutrition also has to include undernutrition. Is it a single concern, or something more complex? We have to consider deficiency of both meats and vegetable sources, and a deficiency of both n-3 and n-6 PUFAs. We also have to consider disuse atrophy from immobility, which would lead to muscle loss. Then we have to consider insufficiency of essential trace metals and enzyme cofactors. One well known associate factor is magnesium. The essentiality of Sulfur can’t be ignored either.
The opening of the genomic explosion is a breath of fresh air. This has to be integrated with key metabolic events.
Dr. Larry, all points are very well taken.
TLR receptors role in Disease and Therapy
TLRs are frequently referred to as a system of non-specific or “innate” immune defense, ie, the response is present and unchanging during the life of the organism and occurs in the same manner with every exposure to the pathogen [3]. This is in contrast to specific or “adaptive” immunity (present only in vertebrates and mediated by lymphocytes), whereby the immune system response changes during the life of the host. Adaptive immune responses may be more vigorous (or suppressed) with each exposure to a pathogen depending upon encounters with that organism or others, and other conditions prevailing in the host. In vertebrates, although TLRs initiate protective functions that operate independently from adaptive immunity, they also modulate mechanisms having profound impact on the development of specific immune responses
TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the “Interleukin-1 Receptor/Toll-Like Receptor Superfamily”; all members of this family have in common a so-called TIR (Toll-IL-1 receptor) domain.
Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for interleukins that are produced by macrophages, monocytes, and dendritic cells and all have extracellular Immunoglobulin (Ig) domains. Proteins with subgroup 2 TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin. A third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2.
TLRs are present in vertebrates, as well as in invertebrates. Molecular building blocks of the TLRs are represented in bacteria and in plants, and plant pattern recognition receptors are well known to be required for host defence against infection. The TLRs thus appear to be one of the most ancient, conserved components of the immune system.
In recent years TLRs were identified also in the mammalian nervous system. Members of the TLR family were detected on glia, neurons and on neural progenitor cells in which they regulate cell-fate decision.[3]
[edit]
TLRs are transmembrane proteins that contain extracellular domains composed of leucine-rich regions that interact with specific PAMP ligands. The cytoplasmic domains of TLRs, which are homologous to the interleukin-1 receptor (IL-1R) signaling domain, are the called Toll/interleukin-1 receptor (TIR) domains. PAMP-specific activation of TLRs converges at the level of TIR domain signaling to induce the activation of NFkappaB and inflammatory gene expression to clear infectious agents. The TIR domain has been linked to five adaptor molecules; MyD88, Mal (MyD88 adaptor-like)/TIRAP (TIR domain-containing adaptor protein), Trif (TIR-domain-containing adaptor inducing interferon-beta), TRAM (Trif-related adaptor molecule) and SARM (SAM and ARM-containing protein).
The TLRs are categorically divided into two membrane receptors groups. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, TLR11, TLR12 and TLR13 are typically associated with the cell surface. TLR3, TLR7, TLR8 and TLR9 are found primarily on endosomal membranes. Phylogenetically the TLRs are divided into six families; TLR1, TLR3, TLR4, TLR5, TLR7 and TLR11. TLRs are differentially activated by a variety of PAMPs such as bacterial DNA, LPS, peptidoglycan, teichoic acids, flagellin, pilin, viral dsRNA and fungi zymosan. For example, TLR2 recognizes soluble peptidoglycan, lipoteichoic acid and whole Gram-positive bacteria and TLR4 responds to the Gram-negative component lipopolysaccharide (LPS). Activated TLRs differentially trigger the expression of cytokines such as the interferons; the interleukins; IL-2, IL-6, IL-8, IL-12, IL-16, and TNFalpha.
Acute lymphocytic leukemia (ALL) is a type of cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made.
see my post on the subject for the role of FLT3 receptor
FLT3 is a receptor tyrosine kinase (RTK) expressed by immature hematopoietic progenitor cells. The ligand for FLT3 is a transmembrane or soluble protein and is expressed by a variety of cells including hematopoietic and marrow stromal cells; in combination with other growth factors, the ligand stimulates proliferation and development of stem cells, myeloid and lymphoid progenitor cells, dendritic cells and natural killer cells. Activation of the receptor leads to tyrosine phosphorylation of various key adaptor proteins known to be involved in different signal transduction pathways that control proliferation, survival and other processes in hematopoietic cells. FLT3 is not only of utmost interest regarding physiological processes of hematopoietic cells but also with regard to pathological aspects, namely leukemogenesis and diagnosis, prognosis and therapy of leukemia. Activating mutations of the receptor have been recognized as the most common genetic abnormality in acute myeloid leukemia (AML), occurring in about 30% of adult cases. AML patients with FLT3 mutations tend to have a poor prognosis, thus FLT3 is an attractive target of therapy, for instance using kinase inhibitors.
FLT3 is implicated with ALL not only AML.
Sunitinib brings Adult acute lymphoblastic leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade
http://pharmaceuticalintelligence.com/2012/07/09/sunitinib-brings-adult-all-to-remission-rna-sequencing/
Targeting cancer with small molecule kinase inhibitors.
Zhang J, Yang PL, Gray NS.
Source
Dana-Farber Cancer Institute, Department of Cancer Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Rev Cancer. 2009 Jan;9(1):28-39.
Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. To date, 11 kinase inhibitors have received US Food and Drug Administration approval as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases that are implicated in cancer and other diseases. Herein we discuss the current challenges in the field, such as designing selective inhibitors and developing strategies to overcome resistance mutations. This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors.
Wow! This is great. It’s a lot to take in, but it gives a great deal of clarity.
Very exiting to note the detailed comments made by Dr. Larry and Dr. Aviva.
my understanding as on today is that as Dr. Larry commented above on
” A medicine that interferes with the metabolism of cancer cells by depriving them of the energy provided by glucose”,
I also do not think that is going to bear healthy fruits.
My strong hope is on (whether it is cancer or any other health condition) nanotechnology related attempts rather. I would like to see science progressing from molecular level to atom(ic) level biology (if at all it is possible) to deal with the disease conditions in a more sophisticated way. How ? I do not know at this point of time but would certainly be exciting to see.
I love the intellectual stimulation among us. You tell me, aren’t we our own competent peer reviewers? if so, our niche is between an Open Journal and a Scientific Publishing venue.