What are some common sites of metastasis of skin cancer?
intestines, lung and brain
What are the drugs for basal cell carcinomas?
What are BCCs typically caused by?
They are usually caused by a combination of cumulative and intense, occasional sun exposure.
Are BCCs likely to metastasize?
BCC almost never spreads (metastasizes) beyond the original tumor site. Only in exceedingly rare cases can it spread to other parts of the body and become life-threatening.
It shouldn’t be taken lightly, though: it can be disfiguring if not treated promptly.
What are the treatment options for BCCs?
-surgical excision (Mohs surgery has the best cure rate)
-photodynamic therapy (aminolevulinic acid)
-targeted therapy (for advanced BCCs)
What is a common signaling mutation in BCCs?
Hedgehog signaling, an important pathway in embryogenesis and organ maturation but one that is typically quiescent by adulthood except for minor tissue maintenance, but can also become dysregulated in some forms of cancer, including BCC.
Hedgehog mutations have also been implicated in what kinds of cancers?
What are some of the pathological consequences of upregulated HH signaling?
-upregulation of anti-apoptotic protein Bcl-2, induction of VEGF and angiogenesis
How do drugs attack abnormal HH signaling?
They (Vismodegib/Sonidegib) must act at or below the level of the transmembrane protein SMO (smoothened) because the pathway is ligand independent, so blocking HH binding to PTCH1 (protein patched homolog 1) is ineffective
What are the AEs of Vismodegib and Sonidegib
-Teratogenic female AND male (makes sense since HH is invovled in organ formation)- up to 20 months after use in women and 8 months in semen in men
-elevated serum creatinine
What drugs are available for squamous cell carcinoma?
What are squamous cell carcinomas?
“Squamous cell carcinoma (SCC) is an uncontrolled growth of abnormal cells arising in the squamous cells, which compose most of the skin’s upper layers (the epidermis). SCCs often look like scaly red patches, open sores, elevated growths with a central depression, or warts; they may crust or bleed. They can become disfiguring and sometimes deadly if allowed to grow.
What are the treatment options for SSCs?
-photodynamic therapy (aminolevulinic acid)
-targeted (afatinib and Cetuximab)
-conventional drugs (bleomycin, docetaxel, hydroxyurea, fluorouracil
What is Afatinib? Cetuximab?
PO irreversible TKI for EGFR and HER2
Cetuximab- EGFR monoclonal bloking phosphorylation and activation of kinases
Toxicities of targeted drugs?
These drugs can affect virtually any organ in the body due to their chronic use resulting in accumulation. Make sure to monitor closely
What are the major toxicities of EGFR ddrugs?
-derm rxns especially common (rash, dry skin, etc.)
-rarely CV toxicity
What are the drug options of actinic keratosis?
What is actinic keratosis?
Actinic keratosis, also known as a solar keratosis, is a scaly or crusty growth (lesion) that most often appears on areas of the body commonly affected by the sun. You’ll often see the plural, “keratoses,” because there is seldom just one. In the beginning, actinic keratoses are frequently so small that they are recognized by touch rather than sight. It feels as if you were running a finger over sandpaper. Patients may have many times more invisible (subclinical) lesions than those appearing on the surface.
What is the typical progression of actinic keratoses?
Most often, actinic keratoses develop slowly and reach a size from an eighth to a quarter of an inch. Early on, they may disappear only to reappear later. Most become red, but some will be light or dark tan, pink, red, a combination of these, or the same color as your skin. Occasionally they itch or produce a pricking or tender sensation. They can also become inflamed and surrounded by redness. In rare instances, actinic keratoses can even bleed.”
If left untreated actinic keratoses can transform into what?
Treatment options for actinic keratoses?
-cyrosurgery is most common
-topical options (5-FU creams such as imiquimod creams and ingenol mebutate)
How does Imiquimod (Aldara) work?
It is an immunostimulant that primarily affects Toll-like receptors (and maybe adenosine receptors) to increase immune responses
AEs of Imiquimod?
-topical site irritation (avoid sunlight)
-can compromise condom and diaphragm integrity when used to treat genital warts
How does Ingenol Mebate work?
The drug produces an interesting biphasic effect. Rapid lesion necrosis begins 1 to 2 hours after application. Specific neutrophil mediated antibody (Ab)-dependent cellular cytotoxicity (ADCC ) follows within several days of drug application. Recall that, in neutrophil-mediated ADCC, Ab are produced by B cells and bind to specific antigens on dysplastic epidermal cells. These Ab also bind to receptors on infiltrating neutrophils. Occupation of receptors on neutrophils by specific Ab triggers neutrophils’ killing mechanisms, including release of cytotoxic agents such as ROS, which destroy dysplastic epidermal cells.
AEs of Ingenol Mebate?
-erythema, skin peeling, swelling, superficial ulceration
(not really systemic)
Melanoma treatment options
What are some roles of IL-2 agonism (aldesleukin)?
IL-2 possesses a potent ability to stimulate cytotoxic T cells and to expand and activate antitumor lymphocyte populations (formerly termed lymphokine-activated killer cells). However, IL-2 also stimulates TReg cells which can diminish the beneficial effects of stimulating tumor- or virus-specific T cell responses. Indiscriminate stimulation is also responsible for the array of adverse drug effects.
AEs of Aldesleukin?
- vascular (capillary) leak syndrome (VLS) which is associated with increased vascular permeability, hypotension, pulmonary edema, liver cell damage and renal failure is considered due either to stimulation of CD122hi NK cells, leading to the release of pro-inflammatory cytokines (such as TNF) and the production of vasoactive mediators, or to the direct binding of IL-2 to CD25+ endothelial cells rather than to NK cells or other CD25−CD122+ cells.
- must be administered (IV bolus) in a hospital setting
-severe lethargy, somnolence, and come
-infection risks due to impaired neutrophils
Contraindications to Aldesleukin?
-restricted to patients with normal pulmonary (PFT normal) and CV function (stress test)
-hepatic or liver disease
-organ transplant (may increase risk of rejection due to improved cellular immune function).
-treat pre-existing infections before giving
Describe the use of the BCG vaccine in melanoma
May be used to stimulation of the patient’s immune system to recognize and eradicate the tumor cells.
How can exogenous interferon (Intron A) be used in melanoma treatment?
Type I interferons (IFNs) activate antitumor immunity. This extrinsic activity includes stimulation of the innate and adaptive cytotoxic lymphocyte populations (T cells, NK cells, dendritic cells, innate lymphoid cells (ILCs)) and the negative regulation of suppressive cell types known to dampen antitumor immunity (for example, myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells). Type I IFNs also have an intrinsic impact on tumor cells by inhibiting proliferation, and modulating apoptosis, differentiation, migration and cell surface antigen expression.
Type I IFNs can be produced by both tumor and immune cells, resulting in activation of immune cells, the actions of which will depend on, or complement, tumor cell intrinsic effects, including antigen presentation, cytokine production and death signaling pathways. As such, the effect of type I IFNs on the reciprocal crosstalk between immune and tumor cells is key to their antitumor potential.
What are the AEs of Intron A?
can affect many organs
-may aggrevate fatal neuropsychiatric, autoimmune, ischemic (CV), and infectious disorders
-worsening of depression
What to monitor with Intron A?
-LFTs can be elevated
-CBCs (can be toxic to blood components)
What are the 'checkpoint inhibitors' used in melanoma treatment?
How are T-cells activated?
It depends on peptide presentation AND co-stimulatory signals to refine the response (CD28 binding by either CD80 or CD86)
How can T-cell response be downregulated normally?
a | The CTLA4-mediated immune checkpoint is induced in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor (TCR)- mediated signalling. High-affinity ligands induce higher levels of CTLA4, which dampens the amplitude of the initial response. The key to the regulation of T cell activation levels by the CD28–CTLA4 system is the timing of surface expression. Naive and memory T cells express high levels of cell surface CD28 but do not express CTLA4 on their surface. Instead, CTLA4 is sequestered in intracellular vesicles. After the TCR is triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent level of T cell activation in the face of widely varying concentrations and affinities of ligand for the TCR.
b | By contrast, the major role of the programmed cell death protein 1 (PD1) pathway is not at the initial T cell activation stage but rather to regulate inflammatory responses in tissues by effector T cells recognizing antigen in peripheral tissues. Activated T cells upregulate PD1 and continue to express it in tissues. Inflammatory signals in the tissues induce the expression of PD1 ligands, which downregulate the activity of T cells and thus limit collateral tissue damage in response to a microorganism infection in that tissue. The best characterized signal for PD1 ligand 1 (PDL1; also known as B7-H1) induction is interferon-γ (IFNγ), which is predominantly produced by T helper 1 (TH1) cells, although many of the signals have not yet been defined completely. Excessive induction of PD1 on T cells in the setting of chronic antigen exposure can induce an exhausted or anergic state in T cells.
So what is the effect of Ipilumumab?
It targets CTLA4 to prevent downregulation of T cell activity for treatment of melanoma and NSCLC
What is the effect of Nivolumab? Pembolizumab?
Nivolumab- targets PD1 for treatment of melanoma and NSCLC
Pemoblizumab- targets PD1 for treatment of PD1
AEs of checkpoint inhibitors?
BBWs- endocrinopathies diarrhea, serious rash, and peripheral neuropathy
-avoid in pregnancy
-immune-mediated AEs such as dermatitis including toxic epidermal necrolysis
Signaling pathways in melanoma
Two important components, BRAF and MEK have been identified as having therapeutic importance. On the one hand we can use PO small molecular weight drugs that are effective against mutated (constitutively active) BRAF, and on the other, separate drugs to block the effects of an important downstream modulator, MEK1/2.
Target of Cobimetinib and Trametinib?
What melanoma drug targets BRAF V600E?
-Debrafenib (and BRAF V600K/D and wild-type BRAF)
What does sorafenib target?
multiple intracelular and cell surface kinases
Some things to consider with oral drugs?
most of these kinase inhibitors are CYP substrates, some weak inhibitors, some interact with food or dependent on acidic environments for uptake
AEs for PO MEK or BRAF inhibitors?
-rash in EGFR TKIs
-decreased LVEF, HTH, thromboembolic states