Sweatman - Skin Cancer Flashcards
1
Q
What 2 drugs are used to treat basal cell carcinoma?
A
Imiquimod and Vismodegib
2
Q
What 3 drugs are used to treat actinic keratosis?
A
Diclofenac, Imiquimod, and Trichloroacetic acid
3
Q
What are the 3 types of skin cancers? Are they treatable? Where do they metastasize?
A
- Basal cell
- Squamous cell carcinoma
- Melanoma
- Most are cured if found and treated early
- Metastatic disease is more resistant to tx, and is the cause of mortality: intestines, lung, brain
4
Q
What is the most unique factor in tx of skin cancers?
A
- Localized disease is amenable to TOPICAL APPLICATION
- Maximizes drug concentration at the tumor site, whilst minimizing drug systematization and potential toxicity
- Downside of this approach is that one may miss more deeply seated malignant cells that subsequently metastasize
5
Q
Basics for tx of BCC
A
- Localized tx: topical Fluorouracil or Imiquimod
- With metastasis: there is no standard regimen, but Cisplatin is probs the most effective single agent
- Hedgehog pathway: Vismodegib
6
Q
Imiquimod
A
- Small molecule tumor-directed immune response initiator (immunostimulant) -> BCC tx
1. Direct activation of TLR 7 and/or 8
2. Adenosine receptor blockade involvement
3. Activation of NFkB: upregulation of cytokines like TNF-alpha and interleukins -
Topical agent w/limited systematization
1. Benzyl alcohol, paraben (preservative) components may be allerginic -> mild-mod localized skin rxns common - INC photosensitivity: pts should be advised to avoid direct sunlight on tx area
- Also used for actinic keratosis and HPV
- Contact can compromise condom and diaphragm integrity: HPV tx -> possibility of compromised birth control on contact w/the drug product
7
Q
What is the “new” MOA of Imiquimod?
A
- BCC is a hedgehog (HH) driven malignancy with glioma-associated oncogene (GLI) signalling activated in a ligand-dependent manner
- IMQ can directly repress HH signalling independent of TLR activity by (-) modulating GLI activity in BCC
- Previously unknown MOA of IMQ in tx of BCC; also suggests a role for ADORAs (adenosine receptors) in the regulation of oncogenic HH signalling
- Remember: original MOA as a TLR7 and 8 agonist initiating Th1 response by activating sentinel cells in the vicinity of the tumour
8
Q
What is hedgehog signalling?
A
- Regulates body patterning during embryogenesis, and organ devo, but quiescent by adulthood, except for role in tissue maintenance and repair
- Inappropriate reactivation linked to several human cancers including BCC, medulloblastomas, and rhabdomyosarcomas
- Aberrant signalling: upregulation of anti-apoptotic BCL-2, induction of VEGF and angiopoietins
- INH act at or below level of transmembrane protein SMO (pathway ligand independent, so blocking Hh binding to PTCH1 surface complex ineffective)
9
Q
Vismodegib
A
- Oral SMO INH; lipophilic agent w/extensive metab
1. Promotes antagonism of pro-proliferative signals from abberant HH pathway activation - Intrauterine fetal death
- Male-mediated teratogenicity
-
Pregnancy status verification: M & F pts need to practice contraception
1. Restrictions on blood donation extend out to 7 months - Alopecia
- GI toxicity (N/V, diarrhea, vomiting) common
- Weight loss, fatigue reported
10
Q
Basics of SCC tx
A
- Treatment does not involve drugs in initial therapy, and there are presently no targeted drugs
- Conventional chemotherapeutics most likely involve the use of Cisplatin, although no standard regimen is presently advocated
11
Q
Basics of melanoma tx
A
- Dismal prognosis: 5-yr survival of 15%
- Conventional chemo: Dacarbazine, Temozolomide have poor response rates (7-20%) and median survival of 9 mos (w/mild toxicity profiles)
- Immunotherapies: IL-2 (16% RR, 8.9 mos) in MM, but assoc w/significant toxicity and limited options for safe and effective tx for disease mgmt
- Checkpoint inhibitors: INC immune surveillance
- Small molecule kinase INH: BRAF muts assoc with a significant # of melanomas
12
Q
Aldesleukin
A
- Binds cell surface IL-2 receptor; IV or SC
- Induces proliferation/differentiation of B and T-cells, monocytes, macros, CTLs, and NK cells via cytokine cascade
- Contra w/significant CNS, cardiac, pulm, renal (BBWs) or hepatic disease, and/or organ transplant recipient (may INC risk of rejection)
1. HypoTN, S-TACH, peripheral vasodil, SVT
2. DEC mental status, speech difficulty, cortical blindness, limb/gait ataxia, hallucinations, agitation
3. Dyspnea, pulm congestion, rales, rhonchi
4. Renal failure/insufficiency via cap leak syn - AEs affect almost every organ system -> can only admin to pts clinically able to tolerate it
1. Ned normal thallium stress test (CV, pulm)
2. Baseline and daily on-tx CXR recommended
13
Q
How does IL-2 affect the immune system? Pros? Cons?
A
- Stimulates CTLs and expands/activates antitumor lympho pops, BUT also stimulates TRegs, which can diminish beneficial effects
- Indiscriminate stimulation also responsible for array of AEs, e.g., vascular cap leak syndrome (VLS)
1. INC vascular permeability, hypoTN, pulm edema, liver cell damage, and renal failure
2. Due either to stimulation of CD122hi NKs, and release of pro-inflammatory cytokines (like TNF) and production of vasoactive mediators, or direct binding of IL-2 to CD25+ endo cells rather than NK cells or o/CD25−CD122+ cells
14
Q
IFN-alpha 2b
A
- Immunomodulator (like endogenous IFN); IV or SC
- Caution in: autoimmune disease, cardiac disease, depression (risk of suicidal ideation), and infection
- Most comm AE flu, flu-like symptoms: fever, fatigue
- Neutropenia, leukopenia, anemia, alopecia
- Elevated hepatic enzymes: routine LFTs required
- Cough and dyspnea; pulm infiltrates, pneumonitis, pneumonia
- Tests: CBC, ECG, CXR, LFTs
15
Q
How does IFN enhance tumor immunity?
A
- Down-regulates the MEK/ERK/MAPK and STAT3, which are involved in cell survival, metastasis, angiogenesis, and immune invasion
- Myriad of complex regulatory effects on T-cells and NK cells -> INC ability to activate CD8+ T’s and promote ability of of NK to directly lyse tumor cells via: perforin, granzyme, and FasL
16
Q
How do the immune checkpoint drugs differ from the traditional drugs in their effects on the immune system?
A
- Goal is to remove the permissive environment surrounding the tumor cells where suppression of normal immuno surveillance provides protection
- In other words, instead of putting more weight on the immunostimulatory side, the aim is to reduce the weight on the immunosuppressive side, perhaps increasing the efficacy of immunostimulant drugs like IFN-alpha
17
Q
What are the 3 checkpoint inhibitors? What do they do?
A
- Ipilimumab: CTLA4
- Nivolumab and Pembolizumab: PD1
- T-cell activation involves a # of co-stimulatory and co-inhibitory signals that modulate the magnitude of effect produce in the activated T-cell
1. PD1 and CTLA4 both co-repressive signals -
Both CTLA4 and CD28 are receptors for CD80 and CD86, so CTLA4 competes for, and has a higher affinity for them
1. Blocking CTLA4 increases the likelihood that CD80 and CD86 will successfully activate CD28, a co- stimulatory signal - Inflam signals in tissues induce expression of PD1 ligand, downregulating the activity of T-cells, and limiting the collateral tissue damage -> blocking this activity can help prevent downregulation
18
Q
What is CTLA4? How does it work?
A
- Key is timing of surface expression
- Naive and memory T cells: high expression of CD28, but CTLA4 sequestered in IC vesicles, and transported to cell surface after TCR trigger w/Ag
- CTLA4 is induced in T-cells at initial response to antigen, and level of induction depends on amplitude of initial TCR-mediated signalling
- Higher levels of CTLA4 (via high affinity ligands) dampen the amplitude of the initial response
21
Q
What are the common AEs with the transduction inhibitors?
A
- HTN only with Sorafenib
- Fever, shivering, and peripheral edema only with Dabrafenib and Trametinib
- Long list reflects importance of inhibited pathways in other, non-tumor tissues, and lack of absolute kinase specificity of small molecule inhibitors
23
Q
Reminder that MEK1/2 proliferative signals from multiple sources -> duplicative pathways responsible for proliferation
A
Good job!
