Hedgehog inhibitors represent a class of targeted therapy drugs primarily used in oncology. These medications function by obstructing a specific cellular communication pathway that, when overactive, can contribute to the growth and proliferation of certain cancer cells. By interfering with this intricate signaling network, these inhibitors aim to slow or halt tumor progression.
The Hedgehog Signaling Pathway
The Hedgehog signaling pathway plays a fundamental role in embryonic development, guiding tissue and organ formation. It also contributes to tissue repair and maintenance in adults. At the cellular level, it directs cell growth and differentiation.
Normally, the pathway remains largely inactive in adults. However, in certain cancers, it can become abnormally reactivated, acting like a “growth switch” stuck in the “on” position. This uncontrolled activation leads to unchecked cell proliferation and tumor growth. Such aberrant signaling often results from gene mutations within cancer cells or the overproduction of pathway-stimulating proteins, fueling tumor survival.
Mechanism of Action
Hedgehog inhibitors target Smoothened (SMO), a key protein in the pathway. Normally, Patched (PTCH1) inhibits SMO activity, preventing signal progression. However, in cancer, mutations in PTCH1 or SMO itself can abnormally activate the pathway, causing SMO to send continuous growth signals.
Hedgehog inhibitors bind to and block the SMO protein. By occupying SMO’s drug-binding pocket, these small-molecule inhibitors prevent it from transmitting signals downstream. This turns off the “growth switch” within cancer cells, preventing them from multiplying and spreading, which can lead to tumor shrinkage.
Medical Uses and Approved Drugs
Hedgehog inhibitors are approved for specific cancers with abnormally active pathways. A primary indication is advanced basal cell carcinoma (BCC), the most common skin cancer. This includes locally advanced BCC that has recurred after surgery or radiation, and metastatic BCC. Vismodegib (Erivedge) was the first FDA-approved Hedgehog pathway inhibitor for BCC in 2012.
Sonidegib (Odomzo) was approved by the FDA in 2015 for similar indications in locally advanced BCC. These oral medications offer a targeted treatment option for patients not candidates for surgery or radiation therapy. Early studies also showed positive responses in patients with medulloblastoma, a pediatric brain cancer commonly associated with Hedgehog pathway mutations.
Beyond BCC and medulloblastoma, Hedgehog inhibitors like glasdegib (Daurismo) are used more broadly. Glasdegib is approved in combination with low-dose cytarabine for newly diagnosed acute myeloid leukemia (AML) in adults aged 75 or older, or those with medical conditions preventing standard chemotherapy. This highlights the pathway’s role in various hematological and solid tumors where its aberrant activation drives disease progression.
Common Side Effects and Management
Hedgehog inhibitors can cause side effects due to the pathway’s normal functions in healthy tissues. Muscle spasms are frequently reported, affecting a substantial percentage of patients. These spasms may occur because SMO inhibitors can activate calcium channels in cell membranes, contributing to muscle contractions. Management strategies include stretching, maintaining electrolyte balance, and sometimes using muscle relaxants under medical guidance.
Hair loss (alopecia) is another common side effect. This occurs because hair follicles rely on Hedgehog signaling for their normal growth cycle, and its inhibition can disrupt this process. Hair loss is typically reversible once treatment ends. Taste alterations (dysgeusia) can also affect patients. Nutritional counseling can help patients find enjoyable foods to maintain proper intake and manage potential weight loss.
Fatigue is a common tiredness that can significantly affect daily activities. Weight loss is also common, linked to reduced appetite from taste changes or other gastrointestinal effects like nausea and diarrhea. Regular follow-ups with healthcare providers are important to monitor these side effects and implement supportive care. Adjusting treatment schedules, such as temporary interruptions, may also help alleviate symptoms without compromising efficacy.
Development of Drug Resistance
Over time, some cancers treated with hedgehog inhibitors can develop resistance, making the drugs less effective as cancer cells bypass their blocking action and continue to grow. A primary reason for this acquired resistance involves new mutations within the SMO protein itself. These mutations can occur in the drug-binding pocket of SMO, preventing the inhibitor from attaching effectively, or they can alter SMO to remain constitutively active despite the drug’s presence.
Resistance can also arise from changes in other parts of the Hedgehog pathway, such as mutations in the PTCH1 gene or the loss of the SUFU protein, both of which normally regulate SMO. Additionally, cancer cells might amplify the GLI transcription factors, which are downstream effectors, allowing them to activate gene expression even when SMO is inhibited. Some cancers may also activate alternative, “non-canonical” pathways that bypass SMO entirely, leading to continued tumor growth.