Targeted Cancer Therapies Flashcards
What was done by Colonel George Beatson in 1896 , Regarding hormonal therapies?
He noticed that removing ovaries and women had to produce tumours in breasts. Oestrogen is produced in the ovaries and he concluded that breast cancer must be linked to the hormone oestrogen however it is not a simple as this. 
What was done in the 1960s by Dr Elwood Jensen?
He discovered the oestrogen receptor, a nuclear protein found in breast cancer cells. They were able to show that the oestrogen receptor was present in around 70% of breast cancer tumours. They developed a diagnostic test to assess the present of the Eastern receptor in biopsy samples.
Taxoxifen
Antiestrogen for female contraception it was useful as a contraceptive however when tested in clinic for breast cancer it showed the shrinkage of 10 tumours out of 42 patients and paved the way for licensing in 1972
The structure of tamoxifen
An antagonist and agonist of the ER receptor inhibiting function of estradiol. Antiestrogenic activity of the compound has been attributed to the metabolism of the active for hydroxy derivative endoxifen
Tamoxifen, how it works?
Tamoxifen is a selective estrogen receptor modulator (SERM) that exhibits a dual antagonist/agonist mechanism of action at the estrogen receptor (ER). Its activity is primarily mediated through its active metabolite, endoxifen.
the Antagonistic Effect of tamoxifen
Tamoxifen acts as an antagonist at the estrogen receptor in certain tissues, such as breast tissue. In these tissues, tamoxifen competes with endogenous estrogen for binding to the estrogen receptor, effectively blocking estrogen signaling. By occupying the estrogen receptor without activating it, tamoxifen prevents the stimulatory effects of estrogen on cell proliferation and growth. This antagonistic action is particularly important in ER-positive breast cancer, where estrogen promotes tumor growth.
The agonist effects of tamoxifen
Interestingly, tamoxifen also exhibits agonistic effects at the estrogen receptor in other tissues, including bone and the endometrium. In these tissues, tamoxifen can activate the estrogen receptor, leading to estrogen-like effects. The underlying mechanism for this agonistic activity is complex and not fully understood. It involves tissue-specific co-regulatory proteins and interactions with other signaling pathways.
Tamoxifen’s Contribution of Endoxifen
Endoxifen is the primary active metabolite of tamoxifen, formed through the metabolism of tamoxifen by the cytochrome P450 enzyme system, particularly CYP2D6. Endoxifen has a higher affinity for the estrogen receptor compared to tamoxifen itself, making it a more potent modulator of estrogen receptor activity. Endoxifen contributes significantly to tamoxifen’s overall efficacy and dual antagonistic/agonistic effects.
ER positive
breast cancer cells that contain the estrogen receptor and can therefore be treated with antiestrogens such as tamoxifen
ER negative
breast cancer cells that do not contain the estrogen receptor and cannot be treated with antiestrogens.
How do we determine ER positive or not?
The biopsy testing procedure, developed by Elwood in the 1970s, is still used today to determine whether patients hare ER-positive or ER-negative breast cancer
what was observed in breast cancer patients?
HER2 was overexpressed and present in unnaturally high levels in many breast cancer patients.
How is HER-2 antibodies selected and treated?
antibodies to selectively bind to HER2, in order to quantify the levels of HER2 overexpression. The same approach was then used to develop a HER2 inhibitor, which wasn’t a small molecule as is typical in drug discovery, but an antibody.
monoclonal antibodies
Antibodies are Y-shaped proteins used by the immune system to target pathogens (or foreign agents), such as viruses. Antibodies selectively recognise antigens, a component of pathogens.
What is major breakthrough with monoclonal antibodies made?
The development of antibodies as biomarkers was made in 1975 when monoclonal antibodies were developed. This technique allows a continuous supply of, selective, identical antibodies to be developed. The term monoclonal refers to the fact that they bind to only one part of the antigen.
Herceptin
The drug Herceptin is a highly effective monoclonal antibody for the treatment of HER2-positive breast cancer, and was licensed in 1998
Rituximab
used to treat non-Hodgkin lymphoma or NHL (the most common form of adult blood cancer), leukaemia and rheumatoid arthritis. It is a monoclonal antibody that inhibits CD20, thus eliminating cancerous (and mature) B cells.
NHL
It most often arises from B cells. This is a particularly difficult target to treat, of course, since if you eliminate a patient’s B cells their immune response would plummet. The breakthrough came when CD20, a protein in B cells was identified as only being present in cancer tumour or mature B cells and not juvenile cells. Thus CD20 could be inhibited without severely compromising a patient’s immune response.
What is the the future direction of anti-CD20 research?
To attach a radioactive moiety, such as iodine-131, to the antibody for increased efficacy. This is particularly important for patients who express low levels of CD20. In 2003, one such drug, tositumomab,
Human Genome Project
In 1990, HGP, officially started. HGP, which is largely funded by the NIH in the US, is an international project to determine the entire sequence of human DNA - over 3 billion base pairs. The first results of the human genome (90% complete) were published in Nature in February 2001. The HGP revealed there to be about 20,500 human genes, far fewer than was originally thought when the project was started. Because all human beings are slightly different, the human genome is an average human genome.
human genome
It acts as a map for researchers to identify key genes and their sequence in order to help identify the cause of disease. Clearly cancer is a prime target for genomics research given that we know that disease starts in our very own genes.
The Cancer Genome Atlas (TCGA)
An international effort to map the genomic changes in 33 types of cancer. Led by the National Cancer Institute (NCI) in the US and the National Human Genome Research Institute (NHGRI) t
Kinases
Enzymes that phosphorylate (add a phosphate group) to proteins or amino acids and thus have been linked to proliferation and cell death
How does the HGP relate to Kinases?
It has resulted in the identification of more than 90 tyrosine kinases.
The link between tyrosine kinase and HER2
It has been implicated in cellular signalling circuits involved in cancer - HER2 is a tyrosine kinase. These proteins can be considered as oncoproteins: proteins that can cause uncontrolled cell growth. Tyrosine kinases selectively phosphorylate tyrosine residues. There are currently over 25 licensed cancer therapeutics that interact with protein kinases.
Immunotherapy
It involves stimulating a patient’s immune response in order to fight disease, such as cancer. This may be by developing synthetic molecules that mimic and boost a component of the immune system.
biologics.
Synthetically-made therapeutic agents
Different cell types are important for immunotherapy:
B and T cells, natural killer cells and macrophages
B cells
They produce highly specific antibodies (Y shaped proteins) that attach themselves to antigens, thereby flagging them for destruction.
T cells:
Cytotoxic T cells. T cells can produce CD4 helper cells that send signals to CD8, which are in turn killer cells that destroys antigens. As an aside, it is CD4 cells that are depleted in HIV.
Natural killer cells:
Cells that scour the body for foreign substances or antigens.
Macrophages:
‘Big hitter’ immune cells that engulf apoptotic cells and pathogens.
Non-specific immune stimulation
don’t target cancer cells specifically but stimulate the immune system to enhance their response to cancer cells. Monoclonal antibodies and cytokines are an example of substances that can be used to stimulate the immune response
Cytokines
They are small proteins made by T cells, B cells and macrophages. They are crucial in the signalling cascade between other immune system cells and blood cells, controlling their growth and activity
Interleukins
A specific group of cytokines that act as chemical signals between white blood cells
Interleukin-2
It is synthetically produced cytokine, used to enhance the normal function of Interleukin-2, which is to stimulate the growth of immune cells. It is one of the most commonly used immunotherapies for advanced kidney cancer and metastatic melanoma.
cytokine vs hormone
Cytokines perform a similar signalling function to hormones. However it’s important to note that whereas hormones are present in the body in concentrations that don’t appreciably fluctuate, cytokines increase rapidly in the event of trauma.
Checkpoint blockade
Overt or uncontrolled immune responses to pathogens or mutated/overexpressed self-antigens can cause inflammatory tissue damage and autoimmune diseases. In order for the immune system to not “over respond” or destroy healthy cells, there are a number of “checkpoints” in place to regulate the immune response. Cancer uses these checkpoints to ‘dampen down’ the immune response towards the cancerous cells. Thus, drugs that block the checkpoint responses can result in an enhanced response from the immune system in eliminating cancerous cells.
Vaccines
Every antigen requires a slightly different antibody (structurally). The human body remembers the structure of all antibodies and can therefore readily make them if the body encounters the same antigen. This is the basis for vaccinations: administering a small amount of antigen in order for the bodies immune response to make the appropriate antibodies, the blueprint of which will be stored if the patient should ever contract that disease.
What is the single biggest issue in developing effective chemotherapeutics?
drug resistance
What are the 2 different categories of drug resistance?
Intrinsic or primary resistance and Acquired resistance
Intrinsic or primary resistance
This is where a patient already has pre-existing physiological factors that will make the therapy ineffective, such as a low expression of a certain protein with which the therapy interacts with. Intrinsic resistance is present before the therapy was every administered. One such example of intrinsic resistance is administering herceptin to a breast cancer patient who is not Her2-positive. Thus the use of modern targeted therapeutics, coupled with genomics to understand the patient, is the best way to avoid intrinsic resistance.
Acquired resistance
It develops as a consequence of administering the therapy. Chemotherapeutics are extremely toxic and tumours are highly adaptable at resisting these chemicals.
Drug resistance Mechanims
Drug resistance affects small molecule and biologic drug development alike, often by the same pathways. Today’s cancer research is focusing on understanding drug resistance mechanisms at a pace. There are many parallels with drug resistance observed in antimicrobials
