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Cell Signal Transduction > Week 12 > Flashcards

Week 12 Flashcards

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1
Q

What was the first licensed monoclonal antibody?

A

Orthoclone OKT3 (muromonab-CD3) which was approved in 1986 for use in preventing kidney transplant rejection

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2
Q

What does most research on monoclonal antibodies focus on?

A

Identifying new targets for development and maximising their efficacy for use in clinical practice

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3
Q

How many monoclonal antibodies have been approved for use in clinical practice?

A

30 monoclonal antibodies

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4
Q

What are the major limitations of monoclonal antibodies in clinical practice?

A

The use of inefficient models for generation, a lack of efficacy and issues of cost-effectiveness

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5
Q

What is the structure and function of an IgG antibody

A

The IgG antibody is a tetrameric quaternary structure that weighs about 150 KDa. It is a large globular protein that is made up of four peptide chains: two identical heavy chains, gamma (𝞬) and two identical lighter chains. The heavy chain weighs about 50 KDa each and the light chain 25 KDa each

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6
Q

What are humanised antibodies?

A

Antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans

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7
Q

What is the aim of the humanisation of antibodies?

A

To produce antibody therapeutics that do not elicit an immune response and are safe for human use, without impacting efficacy

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8
Q

What do the mechanisms of action associated with mAbs include?

A

Direct cell toxicity, immune-mediated cell toxicity, vascular disruption, and modulation of the immune system

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9
Q

What are therapeutic antibodies used for?

A

They primarily serve to protect the body by attacking cancer cells and cells infected with viruses

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10
Q

Where is the amplification of HER2 observed in?

A

Approximately 20% of invasive breast carcinomas, and portends a poor prognosis with an increased risk for disease progression and a decreased overall survival

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11
Q

What does HER2 receptor do?

A

Normally, HER2 receptors help control how a healthy breast cell grows, divides, and repairs itself

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12
Q

What is HER2+ breast cancer?

A

A breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2)

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13
Q

How is trastuzumab developed?

A

Raised murine monoclonal anti- bodies to the extracellular domain of HER-2 and showed that some of these antibodies were capable of inhibiting the growth of cell lines that overexpressed the receptor

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14
Q

What is trastuzumab?

A

A monoclonal antibody used to treat breast cancer and stomach cancer

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15
Q

What does a positive test for HER2 mean?

A

Breast cancer may grow quickly and possibly come back

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16
Q

How can resistance to trastuzumab be explained?

A

By signaling through other HER dimerization

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17
Q

What has been implicated in the resistance to HER2-targeted therapy?

A

Aberrant activation of the PI3K pathway

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18
Q

What is the newest treatment for breast cancer?

A

New drugs, known as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors — which include palbociclib, ribociclib, and abemaciclib — have transformed the standard of cancer treatment by interrupting cancer cell growth, according to an analysis published in 2021 in JCO Oncology Practice

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19
Q

What is trastuzumab-emtansine?

A

An antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the cytotoxic agent DM1

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20
Q

What are some strategies to overcome resistance of trastuzumab?

A

Development of antibody-drug conjugates, dual HER2 inhibition strategies, inhibition of PI3K/mTOR pathway and development of modulators of immune checkpoints

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21
Q

What percentage of breast cancers overexpress human epidermal growth factor receptor 2?

A

Approximately 15-23%

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22
Q

What does the overexpression of HER2 lead to?

A

The activation of signaling pathways that stimulate cell proliferation and survival

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23
Q

What is T cell checkpoint?

A

T cells have proteins on them that turn on an immune response and other proteins that turn it off

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24
Q

What are the roles of PD-1 and CTLA4 in inhibiting immune response?

A

The roles of CTLA-4 and PD-1 in inhibiting immune responses, including antitumor responses, are largely distinct. CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes, whereas PD-1 suppresses T cells later in an immune response, primarily in peripheral tissues

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25
What is the relationship between PD-1 and T cells?
PD-1 inhibits T cell responses
26
What are the characteristics of PD-1?
PD-1 has one immunoreceptor tyrosine-based inhibitory motif (ITIM) at Y223 and one immunoreceptor tyrosine-based switch motif (ITSM) at Y248. Only ITSM-Y248 is indispensable for PD-1-mediated inhibitory function but how SHP-2 enzymatic activation is mechanistically regulated by one PD-1 phosphotyrosine remains a puzzle
27
What are the different variations found in cancer immunotherapy?
The checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have been validated and are currently used in the clinics
28
What are therapeutic antibodies often associated with?
Significant side effects and are known to induce immune-related toxicities
29
How do immune checkpoint inhibitors work?
Blocking checkpoint proteins from binding with their partner proteins
30
What are the the current first-line systemic therapies for patients with metastatic melanoma?
Anti–PD-1, alone or in combination with anti–CTLA-4, and targeted BRAF therapies
31
What are antibody based therapies?
Monoclonal antibody drugs are treatments that enlist your body's germ-fighting immune system against diseases, including cancer
32
Which drugs are used for the targeted cancer therapies?
Alemtuzumab (certain chronic leukemias) Trastuzumab (certain breast cancers) Cetuximab (certain colorectal, lung, head and neck cancers)
33
How receptor tyrosine kinases act?
As signal transducers that mediate cell-to-cell communication by phosphorylating tyrosine residues on key intracellular substrate proteins
34
What are the largest class of receptors that activate inherent enzymatic activity?
Receptor Tyrosine Kinases
35
What is cross-phosphorylation?
When signaling molecules bind to RTKs, they cause neighboring RTKs to associate with each other, forming cross-linked dimers. Cross-linking activates the tyrosine kinase activity in these RTKs through phosphorylation — specifically, each RTK in the dimer phosphorylates multiple tyrosines on the other RTK
36
Why is the development of covalent inhibitors considered to be a less attractive strategy for rational drug design?
Due to safety concerns and the complexity of their development
37
How is protein kinase A inhibited?
Through PKI binding to the free C subunit of PKA and inhibiting the phosphorylation of PKA substrate
38
What has changed the landscape for the treatment of chronic myelogenous leukemia (CML) and cancer in general?
The development of inhibitors against Abl
39
What is the biggest asset of inhibitors nilotinib and dasatinib?
They are active against many of the mutations in the Abl kinase that confer resistance to imatinib
40
What does EGFR belong to?
The ERBB family of tyrosine kinase receptors
41
What is a key regulator in cell proliferation, differentiation, division, survival, and cancer development?
EGFR signalling cascade?
42
Where is EGFR expressed?
In a variety of human tumors, including those in the lung, head and neck, colon, pancreas, breast, ovary, bladder and kidney, and in gliomas
43
What is non small cell lung cancer?
One of two major types of lung cancer that can affect smokers and non-smokers
44
What inhibitors have been developed to affect EGFR functional activation?
Erlotinib (Tarceva) and gefitinib (Iressa) are two orally bioavailable, small molecule EGFR inhibitors of the tyrosine kinase enzymatic activity which prevent EGFR autophosphorylation and activation
45
What is the expression of EGFR often associated with?
Increased tumour cell motility– Increased adhesion Increased metastatic potential Increased vascularity Chemotherapy resistance Reduced survival
46
When were EGFR mutations in NSCLC cells first discovered?
2004
47
Where do the majority of EGFR mutations occur in NSCLC cells?
In exons 18– 21 of the tyrosine kinase domain of the receptor
48
What can mutations in the G-loop region lead to?
Destabilization of the inactive conformation and stabilization of the active conformation
49
What was the percentage of NSCLC patients found with EGFT mutations?
31.6%
50
What is erlotinib?
A medication used to treat non-small cell lung cancer and pancreatic cancer
51
What is the most common mechanism of acquired resistance to EGFR TKIs?
Acquired T790M mutation
52
How can resistance to EGFR TKI be overcome?
Drugs targeting different kinase binding sites, including allosteric inhibitors, ATP-competitive inhibitors, and “dual-site” inhibitors that occupy both the ATP binding site and an allosteric site
53
What is osimertinib approved for by the US Food and Drug Administration?
For the treatment of patients with exon 19 deletion- or exon21 L858R mutation-positive advanced non–small-cell lung cancer (NSCLC) not previously treated for advanced disease
54
What was osimertinib designed for?
To target both sensitizing and resistant mutant forms of EGFR, but not the wildtype protein, in an effort to improve safety and efficacy compared with other standard of care (SoC) EGFR inhibitors
55
What was osimertinib initially approved for?
In the second-line setting in NSCLC following failure of prior EGFR inhibitor therapy in 2015
56
What is drosophila melanogaster?
A species of fly in the family Drosophilidae
57
What type of signaling is hedgehog?
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation
58
What is the Sonic Hedgehog signalling?
One of the major trafficking networks that regulates the key events during developmental processes i.e growth and patterning of multicellular embryos
59
What explains the different type of digit abnormalities on the hands?
Misexpression of the Shh gene
60
What are the heterogenous causes of holoprosencephaly?
Mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder
61
What is the function of the SHH gene?
The SHH gene provides instructions for making a protein called Sonic Hedgehog
62
What is the cilium?
Short eyelashlike filament that is numerous on tissue cells of most animals and provides the means for locomotion of protozoans of the phylum Ciliophora
63
What hedgehog signalling molecules are found in mammals?
Three ligands (Sonic hedgehog—Shh, Indian hedgehog—Ihh and Desert hedgehog—Dhh), two receptors (PTCH1, PTCH2), a key signal transducer smoothened (SMO) and three transcription factors (Gli1, Gli2, Gli3)
64
What does primary cilia have an essential role in?
An essential role in Hedgehog (Hh) signaling in mammals
65
Where id the discovery of the relationship between primary cilia and hedgehog signalling come from?
Screens in the mouse that identified a set of genes that are required for both normal Hh signaling and for the formation of primary cilia
66
How does Hh signalling promote cancer?
At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells
67
What cancer can be caused by errors in hedgehog communication?
Medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common cancer in the United States
68
What is aberrant activation of Hh associated with?
Neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers
69
What has Hh signalling been shown to drive at the molecular level?
The progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells
70
What are the different type of Hh cancers?
Digestive tract, colorectal, prostate, liver, breast, ovarian, and brain cancer and melanoma
71
Where was the hedgehog signalling pathway first discovered?
In the fruit fly
72
What are the components of the Hh signalling pathway that are involved?
The signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP)
73
Where does the activated form of Gli travel to?
The nucleus and stimulates the transcription of the target genes by binding to their promoters
74
What are the main target genes of the Hh signalling pathway?
PTCH1, PTCH2, and GLI1
75
What is the deregulation of the Hh pathway associated with?
Developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas
76
What Hh signalling inhibitors have been developed to treat cancer?
Vismodegib and sonidegib
77
What is medulloblastoma?
A primary central nervous system (CNS) tumor
78
What are the 4 subtypes of medulloblastoma?
Classic, desmoplastic, anaplastic, large cell, and MB with extensive nodularity (MBEN)
79
What are the treatment options for medulloblastoma?
Radiation, chemotherapy, or taking part in clinical trials
80
What have the mouse models of medulloblastoma proven to be instrumental in?
Understanding disease mechanisms, particularly the role of epigenetic and molecular drivers, and establishing appropriate preclinical pipelines
81
What smoothened inhibitors are prove to have high anti-tumour efficacy?
GDC-0449/Vismodegib and LDE225/Sonidegib
82
What percentage of MB diagnoses were found to have hyperactivation of the Hh signalling pathway?
30%
83
What is a major hurdle in current cancer management?
Resistance to therapy
84
What do cancer cells often rewire?
Their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches
85
What are some mechanisms of resistance to SMO inhibitors?
Genetic mutations including SMO mutation, loss of SUFU, and amplification of GLI or Hh target genes Activation of non-canonical Hh pathway Loss of primary cilia
86
What does non-canonical hedgehog signalling refer to?
All those cellular and tissue responses to any of the Hh isoforms that are independent of transcriptional changes mediated by the Gli family of transcription factors
87
What protein kinases work in the regulation of Hh signalling?
Protein kinase A (PKA), glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1)

Cell Signal Transduction (12 decks)

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