Injectable Therapies for Regional Melanoma.
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ABSTRACT:
SUBMITTER: Farrow NE
PROVIDER: S-EPMC7274146 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The incidence of melanoma has been increasing at a rapid rate, with 4%-11% of all melanoma recurrences presenting as in-transit disease. Treatments for in-transit melanoma of the extremity are varied and include surgical excision, lesional injection, regional techniques and systemic therapies. Excision to clear margins is preferred; however, in cases of widespread disease, this may not be practical. Historically, intralesional therapies were generally not curative and were often used for palliation or as adjuncts to other therapies, but recent advances in oncolytic viruses may change this paradigm. Radiation as a regional therapy can be quite locally toxic and is typically relegated to disease control and symptom relief in patients with limited treatment options. Regional therapies such as isolated limb perfusion and isolated limb infusion are older therapies, but offer the ability to treat bulky disease for curative intent with a high response rate. These techniques have their associated toxicities and can be technically challenging. Historically, systemic therapy with chemotherapies and biochemotherapies were relatively ineffective and highly toxic. With the advent of novel immunotherapeutic and targeted small molecule agents for the treatment of metastatic melanoma, the armamentarium against in-transit disease has expanded. Given the multitude of options, many different combinations and sequences of therapies can be offered to patients with in-transit extremity melanoma in the contemporary era. Reported response and survival rates of the varied treatments may offer valuable information regarding treatment decisions for patients with in-transit melanoma and provide rationale for these decisions.
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Project description:Advances in the biology of melanoma have provided insights about chemoresistance and its genetic heterogeneity in parallel with advances in drug design, culminating in recent major treatment breakthroughs. Although clinical benefit of targeted therapies has been unquestionable, future advances are only possible if we understand the interplay between genetic aberrations and role of other crucial nongenetic changes yet to be identified by such projects as the Cancer Genome Atlas Project in Melanoma. Combination therapies, either among small molecule inhibitors themselves and/or with immunotherapies, may be the optimal strategy to prevent development of drug resistance inherently linked with such targeted therapies.
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Project description:In-transit melanoma is an uncommon pattern of recurrence, but presents unique management challenges and opportunities for treatment. The clinical presentation usually involves from 1 to more than 100 small subcutaneous or cutaneous nodules, ranging from submillimeter to multiple centimeters in diameter. Regional chemotherapy techniques are a mainstay of treatment of patients without systemic disease spread. Future applications of regional therapy are likely to involve combination therapy with cytotoxic agents and novel immune modulators. Regional therapy provides distinct opportunities for the treatment of unresectable disease, and offers a unique platform for investigation of novel therapeutics in early-stage clinical trials.
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Project description:Until recently, melanoma represented a significant clinical challenge to oncologists. However, the approval in 2011 of ipilimumab, an anti-CTLA4 monoclonal antibody, and vemurafenib, a BRAF inhibitor, completely changed melanoma management, with both drugs being shown to improve overall survival. The advent of these two drugs, together with the ongoing development of other targeted agents (e.g., MEK inhibitors) and immunotherapeutic compounds (e.g., anti-PD-L1), is providing the opportunity to trial new combination or sequential therapy approaches. Combined approaches of these new agents with surgery, radiotherapy and/or chemotherapy are also being assessed. Targeted agents in combination or in sequence with new immunotherapeutic compounds may represent the future, not only for the treatment of melanoma, but also for the treatment of cancer in general.
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Project description:Knee osteoarthritis is a common painful degenerative condition affecting the aging Canadian population. In addition to pain and disability, osteoarthritis is associated with depression, comorbid conditions such as diabetes, and increased caregiver burden. It is predicted to cost the Canadian healthcare system $7.6 billion dollars by 2031. Despite its high cost and prevalence, controversy persists in the medical community regarding optimal therapies to treat knee osteoarthritis. A variety of medications like nonsteroidal anti-inflammatories and opioids can cause severe side effects with limited benefits. Total knee arthroplasty, although a definitive management, comes with risk such as postoperative infections, revisions, and chronic pain. Newer injectable therapies are gaining attention as alternatives to medications because of a safer side effect profile and are much less invasive than a joint replacement. Platelet-rich plasma is beginning to replace the more common injectable therapies of intra-articular corticosteroids and hyaluronic acid, but larger trials are needed to confirm this effect. Small studies have examined prolotherapy and stem cell therapy and demonstrate some benefits. Trials involving genicular nerve block procedures have been successful. As treatments evolve, injectable therapies may offer a safe and effective pathway for patients suffering from knee osteoarthritis.
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Project description:Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. However, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. The discovery of BRAF mutations in melanoma created the first opportunity to develop oncogene-directed therapy in this disease and led to the development of compounds that inhibit aberrant BRAF activity. A decade later, vemurafenib, an orally available and well-tolerated selective BRAF inhibitor, ushered in a new era of molecular treatments for advanced disease. Additional targets have been identified, and novel agents that impact on various signaling pathways or modulate the immune system hold the promise of a whole new therapeutic landscape for patients with metastatic melanoma. One of the major thrusts in melanoma therapy is now focused on understanding and targeting the network of signal transduction pathways and on attacking elements that underlie the tumor's propensity for growth and chemoresistance. In this article, we review the novel targeted anticancer approaches that are under consideration in melanoma treatment.
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Project description:Opinion statementBrain metastases are a major clinical challenge occurring in up to 60% of patients suffering from metastatic melanoma. They cause significant clinical symptoms and impair the overall survival prognosis. The introduction of targeted therapies including BRAF and MEK inhibitors as well as CTLA-4 and PD-1 axis targeting immune checkpoint inhibitors have dramatically improved the treatment and prognosis of patients with extracranial metastatic melanoma. Although, similar response rates for extra- and intracranial metastases have been reported, only few data from brain metastasis specific trails are available so far. The following review will provide an overview on the currently available data on targeted therapies, remaining questions and the most important side effects in the special clinical situation of melanoma brain metastases.
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Project description:Melanoma is one of the most aggressive forms of skin cancer, with limited therapeutic options. Since its incidence has been rapidly rising in recent years, the study of new targeted therapeutic strategies has increased. The implication of nanoscience in the development of alternative targeted therapies for melanoma has multiple benefits and could significantly improve the outcome of melanoma patients. In this paper, we review the most recent progress in the field of targeted therapies, emphasizing the impact of nanoscale materials on the targeting and controlled release of anti-tumor drugs. The applications of nanomedicine in the management of melanoma are extensive and refer to sentinel lymph node mapping, chemotherapy, and RNA interference; each of these applications harboring the potential to develop efficient and personalized diagnostic techniques and therapies. Further research, especially in clinical trials, is needed to establish whether fighting melanoma on the nanoscale level represents the key to reaching a critical inflection point in mankind's battle with metastatic melanoma.
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Project description:IntroductionTherapies targeting immune checkpoints (CTLA-4) and the MAP kinase signaling pathway (RAS/RAF/MEK/ERK) have transformed the treatment of advanced melanoma in the past year. Agents aimed at other therapeutic targets of interest are being actively evaluated in the clinic.Areas coveredAreas of active therapeutic interest in melanoma include immunotherapy, molecularly targeted therapy and chemotherapy; combinations of these modalities are now under systematic exploration.Expert opinionThe evaluation of patients with melanoma now includes the molecular profiling of tumor mutations in the BRAF, as well as c-Kit, NRAS and other genes that have been discovered to be drivers of different subsets of the disease. The analysis of the host immunological response to melanoma is equally important, as a basis for the development of immunotherapies that have been of value to melanoma patients in the adjuvant arena, as well as for therapy of metastatic disease. The understanding of these two facets of the disease will provide a more rational basis for the delivery of individualized therapy for the disease both in its advanced setting, and in the adjuvant arena, in the future.
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Project description:Novel therapeutic agents introduced over the past decade, including immune checkpoint inhibitors and targeted therapies, have revolutionized the management of metastatic melanoma and significantly improved patient outcomes. Although robust and durable responses have been noted in some cases, treatment is often limited by innate or acquired resistance to these agents. This article provides an overview of known and suspected mechanisms involved with acquired resistance to BRAF/MEK inhibitors as well as developing insights into innate and acquired resistance to checkpoint inhibitors in patients with melanoma.
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