New Cancer Therapies Flashcards
For lectures 1-4 make sure you go over the paper notecards
- JUST DO IT
When can surgery, chemotherapy, and radiation not be enough?
- For particularly aggressive, metastatic diseases
What types of differences do cancer therapies tend to exploit?
- MACRO differences
- E.g. proliferative rates, DNA synthesis rates, inefficient repair of damage
When do cancer treatments that exploit macro differences have a high therapeutic index?
- Genomic stability
- Rapid cell turnover (e.g. liquid tumors)
What are novel targets for cancer therapies?
- Signal transduction**
- Angiogenesis
- Evasion of apoptosis
- Immune tolerance
- Cell cycle dysregulatio n(harder)
- Tissue invasion and metastasis (harder)
Which are the best possible novel targets?
- Signal transduction
- Evasion of apoptosis
- Angiogenesis
- Immune tolerance
Signal transduction in tumors
- Aberrant signal transduction elements are present in most tumors
- Mutated signal proteins are often oncogenic
- Constitutive activation of signaling elements canc onfer autonomy
- Cell is getting turned on inappropriately
Aberrant expression of growth receptors in tumors relates to these two areas
- Increased potential for proliferation, invasion, and metastasis
- Increased angiogenesis
What are three outcomes changed by aberrant expression of growth receptors related to potential for proliferation/invasion/metastasis and angiogenesis?
- Shortened survival of patients
- Poor response to standard chemotherapy
- Poor prognosis
What are receptor tyrosine kinases?
- Main mediators of the signaling network that transmits extracellular signals into the cell
What do receptor tyrosine kinases control?
- Cellular differentiation and proliferation
How do RTKs relate to cancer?
- Constitutive RTK signaling –> dysregulated cell growth –> cancer
Three ways that RTKs can be altered to dysregulate cell growth?
- Overexpression
- Functional alterations caused by mutations in the corresponding genes (gain of function)
- Abnormal stimulation by autocrine growth factor loops and increased stimulation.
RTK homology
- Homology in the protein tyrosine kinase domain (intracytoplasmic)
- The outsides are quite different, but they often do very similar things inside of the cell
What are the three families targeted by tyrosine kinase inhibitors?
- EGFR-HER-2
- C-kit
- VEGFR
EGFR-HER-2 family
- Epidermal growth factor receptor
- TKR
C-kit family
- Proto-oncogene coding for an RTK
VEGFR family
- Vascular endothelial growth factor receptor
Which tumors contain C-kit mutations?
9-33% of MCTs
- Higher tumor grades associated with more frequent C-KIT mutations (30-50% of grade II/III MCTs contain mutations
What are the two primary RTK inhibitors?
- Toceranib
- Masitinib
Which RTK inhibitor is licensed in the US?
- Toceranib
Toceranib response and duration of response?
- Overall response in grade II tumors was 40%
- Duration was ~12 weeks
Side effects of toceranib and masitinib?
- GI and potential bone marrow suppression from both
How long are animals on toceranib and masitinib?
- Once started continue for life or until lack of effect
Other drugs that might respond to tyrosine kinase inhibitors?
- Thyroid carcinoma
- Anal gland adenocarcinoma
- With piroxicam
- Head and neck carcinomas
- Metastatic osteosarcoma
- OSA - post amputation, no help over traditional therapy
- HSA, soft tissue sarcoma
- Lymphoma, histiocytic SA
TKI and cats with vaccine associated fibrosarcoma?
- VAS cell line
- Inhibits PDGF-induced phosphorylation receptor
- Decreased cell proliferation and apoptosis
TKI and cats with squamous cell carcinoma
- Modest activity
What aspect of the metastasis cascade do anti-angiogenic agents impact?
- Establishment of new growth
Reminder: what are the five aspects of the metastasis cascade?
- Cell detachment and vascular invasion
- Transport and survival in circulation (evasion of host defense)
- Aggregation with platelets and fibrin and arrest in new location
- Extravasation into surrounding parenchyma
- Establishment of a new growth
At what point is tumor growth dependent on vascular growth and neovascularization?
- > 1 mm cubed
- Delivery of nutrients, growth factors, hormones, oxygen
- Removal of wastes and toxins
- Immune surveillance
Is tumor vasculature similar to normal vasculature?
What is the significance of this?
- No, they are quite different
- This is why tumor endothelium represents a valuable target for cancer therapy
VDAs - what are they and what do they do?
- Preferentially destroy ESTABLISHED tumor blood vasculature
- Vascular disrupting agents
When are VDAs given (think the interval)?
- Given only intermittently
- Designed to induce rapid and selective vascular shutdown in tumors
When are agents given that suppress endothelial cell growth and recruitment from bone marrow?
- Continuously
- Mostly when the tumor burden is low
Two modes of targeting tumor blood vessels
- Destroy ESTABLISHED tumor blood vasculature
2. Suppress endothelial cell growth and recruitment from bone marrow
What are the two categories of drugs that target tumor blood vessels?
- Biologics
2. Small molecules
What are biologics?
- Antibodies or peptides that deliver toxins and procoagulant and pro-apoptotic effectors to tumor endothelium
What are the small molecule drugs?
- Agents that exploit known differences between tumor and normal endothelium to induce severe vascular dysfunction
- Often blocking receptors
Examples of small molecule drugs
- Thalidomide (cannot use anymore)
- Toceranib (inhibits VEGF)
What is often the target of biologic drugs?
- VEGF
Avastin
Antibody directed at human VEGF
Biologic
Are there any biologic anti-tumor blood vessels?
- No such drugs yet for veterinary use
What are the two main veterinary strategies for targeting tumor blood vessels?
- Toceranib
2. Metronomic chemotherapy
How does toceranib target tumor blood vessels?
- Direct inhibitor of VEGF signaling
How does metronomic chemo work to target tumor blood vessels?
- Low dose daily dosing of traditional drugs
- Theory is that the drugs stop endothelial cells from multiplying in and homing to neoplastic tissues
Using drugs that target tumor blood vessels?
- Clinical trials alone and in conjunction with chemotherapy or radiation therapy
- Toceranib and radiation for nasal tumors - extended survival
When are drugs that target tumor blood vessels most useful?
- Most effective in prevention of metastasis or tumor regrowth
Which drugs are used for metronomic chemotherapy in general?
- Alkylator class (given orally)
- Plus satraplatin (oral platinum agent)
Chlorambucil metronomic chemo
- For TCC
Cyclophosphamide metronomic chemo
- Soft tissue sarcomas
- In mouse model, stimulates expression of Th17 cells and favors pro-inflammatory immune response as well as anti-angiogenesis
Lomustine metronomic chemo
- Renal and hepatic toxicity
Satraplatin metronomic chemo
- Platinum agent
- Expensive
What are the two pathways for apoptosis?
- Intrinsic (mitochondrial)
- Extrinsic (receptors)
Intrinsic apoptosis - which types of therapies affect it?
- Affected by conventional therapies
- Mutations commonly occur rendering tumors resistant to conventional therapies
Extrinsic apoptosis - which types of therapies affect it?
- Novel therapies may circumvent resistance
- HOWEVER, not known yet if it’s a valid therapy site
How do tumors avoid the immune system?
- Via variety of mechanisms likely, but above all they are recognized as self
Theory behind immune therapy?
- Get the immune system to recognize a tumor as something to destroy
Three main ideas of immune therapy
- Active nonspecific immune stimulation
- Active specific (tumor vaccines)
- Passive (antibody administration)
Examples of non-specific immune therapies
- Intact bacteria or cell components
- Growth factors
- Chemical agents (levamisole, cimetidine, COX-2 inhibitors)
- Vitamins/minerals
- IL-2, IFN-alpha
Examples of active-specific vaccines
- Genetically engineered antigen source designed to stimulate and immune response against an established tumor
Which other agents are incorporated along with the antigen source to induce inflammation in Active specific tumor therapies?
- Cytokines
- Molecules, cells, or cell lysates
- Adjuvants, haptens
Goal of immunotherapy vaccine
- Activate T-cells (increase MHC on cell surface)
2. Activate antigen presenting cells
Melanoma vaccine - what’s the source of the melanoma differentiated antigen?
- Murine tyrosinase DNA
- Human GM CSF for extra immune boost
License for melanoma vaccina
- Dogs with oral melanomas
- Could work in cats and horses
Main side effect of melanoma vaccine
- Tyrosinase - turns white
- Recent studies throwing doubt on efficacy, which is the real issue
Passive immunotherapy examples and general efficacy
- Monoclonal antibodies specific for a tumor (MUST be specific)
- There was one for lymphomas
- Not likely effective
- Some target specific antibodies (VEGF, RTK)
How are T-reg cells involved in cancer promoting?
- T-reg cells destroy the immunosuppressive environment around the drug
Ways to target T-reg cells so that they STOP doing their job?
- Metronomic chemo
- Cimetidine
Gene therapy theory
- Correct the genetics of the tumor, e.g. inhibit oncogenes, stimulate/replace tumor supprssor genes
- Stimulate cytokine production
Limitations of targeted gene therapy as a cancer treatment
- Transduction efficiency
- Can’t really get it to the cell
COX-2 inhibitors - which was the first one discovered?
- Piroxicam
- Discovered in dogs with OSA
- Helped dogs with Transitional cell carcinoma
Cyclooxygenase overview
- Key enzyme in the conversion of arachidonic acid to prostanoids
- PGs and TXs produced in many tissues and involved in many biologic responses
- COX-1 and COX-2
What induces COX-2 in cancer?
- Pro-inflammatory cytokines
- Growth factors
- Mitogenic substances
- Oncogenes
- Hypoxia
Which prostaglandin is the primary culprit for tumor promoting activities?
- PGE2
How does PGE2 promote tumors?
- Conversion of pro-carcinogens to carcinogens
- Stimulate tumor cell growth
- Prevention of apoptotic cell death
- Promote angiogenesis
- Immune suppression
COX-2: more expressed in carcinomas or sarcomas?
- Mostly carcinomas
- Melanomas possibly in equine
- mammary tumors too
Prixociam alone use
- SCC oral cavity in dogs and cats
- Nasal tumors and piroxicam
- Inflammatory mammary carcinoma
Piroxicam plus chemo
- Cisplatin for oral SCC
- Carboplatin for oral non-tonsilar SCC
- Low dose cyclophosphamide for incompletely resected soft tissue sarcomas
Which tumor types have greatest tumor reduction with long-term NSAID therapy?
- Carcinomas and mast cell tumors
COX-2 in cats?
- Few studies but no reason not to give for many carcinomas (TCC< mammary, GI)
- Avoid oral rimadyl
Which COX-2 inhibitors are considered the best to give to cats?
- Meloxicam or piroxicam are easiest
- Meloxicam labeled with warning (but is liquid)
- Onsior
- Galliprant
Selective COX-2 better?
- Don’t need a broad spectrum
- Just want COX-2
- Firocoxib and deracoxib (selective COX-2) works pretty well too
- These are theoretically better
