Sean E. Lawler PhD from Brown University Cancer Center, an experienced scientist in the brain tumour field, details the importance of matching therapies to patients
As an experienced scientist in the brain tumour field, I am often approached by patients who have a brain cancer diagnosis or their family members. One thing I advise is for patients to talk to their care team about clinical trials – this is where the next breakthroughs will come from, and we will only learn more from participation in these studies. Clinical trial data are particularly important because it is not uncommon to see occasional patients responding to therapy; however, the reasons at the molecular level are often unclear. Contemporary trials include a range of molecular correlates and their data increasingly show that it may be possible to improve patient responses by matching them to the appropriate therapy. Thus, a detailed molecular understanding of patient disease and other factors may assist in identifying optimal personalised therapeutics for each patient.
Recent examples as described below show how encouraging responses have been seen in subgroups of patients with this challenging disease. However, brain cancer remains a devastating disease, and new therapies are urgently needed to improve outcomes. In aggressive brain tumours like glioblastoma, there has been little improvement in patient outcomes in decades, despite large numbers of clinical studies and monumental leaps in our understanding of the cellular and molecular nature of these diseases. The standard of care of surgical tumour resection followed by chemotherapy and irradiation has been in place for well over ten years, and is administered to the great majority of patients. There is little doubt that at some point in the future, treatments will be better than this as we unlock complex biology and overcome barriers to therapy. Here, we will take a look at some promising recent early and mid-stage clinical trials that show routes to potential progress over the established standard of care. The examples below are not intended to be exhaustive and show that some therapies may have efficacy in definable disease subgroups.
New therapies are often applied alongside the standard of care. First, mentions should go to existing options, including anti-angiogenic therapy with the drug Avastin which continues to find a place in brain cancer treatment, despite not showing extended survival in Phase 3 clinical trials completed several years ago. Nonetheless, Avastin improves progression-free survival and has effects on tumour biology that may be useful in combination with other drugs. Approved by the FDA in 2011, Tumour Treating Fields (TTF), involve the application of alternating electrical fields to tumours via a wearable device and showed benefits in clinical trials.
Targeted therapeutics are small molecule inhibitors of drivers of tumour growth and have shown extraordinary successes and approvals for some cancer types. However, these approaches can be thwarted by the emergence of resistance mechanisms, where tumours recur that are resistant to the drug through the acquisition of new mutations. Furthermore, brain cancer protection from systemic therapies by the blood-brain barrier can prevent these types of drugs from working properly. Despite a succession of negative clinical trials, some recent papers in brain cancer show responses in molecularly-defined patient subgroups. A recent trial in glioma patients carrying a mutated protein called V600E BRAF showed encouraging outcomes using a targeted inhibitor. Another small molecule anti-cancer drug, ONC201, showed tumour shrinkage in a subset of brain tumours, the diffuse midline gliomas which carry a unique mutational profile. This is a potential breakthrough for such a challenging indication, and is being tested in larger patient cohorts. Thus, after many years of frustration, encouraging data are emerging for small molecule therapeutics, in specific patient subsets.
Immunotherapies have led to remarkable responses in some tumour types, but in brain cancer more work is needed to understand how to apply these approaches effectively. Generally, brain tumours have been refractory to these approaches, but studies continue to explore how immunotherapy could be tuned for greater efficacy. In fact, positive responses have been seen and recent studies have identified biomarkers indicative of responses that will be tested in larger trials. Oncolytic viruses have been suggested to cure a subset of patients via an immune response, and the underlying mechanisms are under investigation. Other cell-based immunotherapies have shown encouraging responses in subsets of patients and immunotherapies targeting a virus called Cytomegalovirus (CMV) have shown some encouraging responses.
Drug repurposing is an approach in which drugs used for one indication may be applied to others. In brain cancer, a myriad of preclinical studies have shown tumour killing effects of a range of drugs that have been used for other indications. A good example of this is the anti-viral drug valganciclovir, which is normally used to treat Herpes virus infections, and in the case of GBM has been given to many patients in a recently published clinical study from the Karolinska Institute in Sweden. This study showed extended median survival in patients given standard of care with add-on valgancilcovir, and may be linked to the role of CMV in promoting tumour growth in the brain, and also the reactivation of CMV in the brain of patients undergoing therapy. This suggests a role for this specific therapy in patients who are infected with CMV. These studies and others show some encouraging signs, however, so far successes are only seen in subsets of patients and larger trials are needed.
A glance at the brain tumour literature reveals an enormous number of preclinical concepts supporting the testing of a range of approaches. Many of these will not make the jump to patients, because of the many challenges involved in drug development. Identifying the appropriate patient populations and effective drugs and combinations could be a painstaking process, but with modern molecular techniques and analysis, these can be readily identified. It is becoming clear that the clinical trial setting with careful tissue archiving and blood collection and analysis will uncover the answers for which we are searching.
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© 2019. This work is licensed under CC-BY-NC-ND.
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