combined pik3ca and fgfr inhibition with alpelisib and infigratinib in patients with pik3ca mutant solid tumors with or without fgfr alterations

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor–positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed

Pathogenic changes and compensatory responses in a model of age-related neurodegeneration

Lysosomes are part of a dynamic system that is involved in replenishing a variety of cellular components. The more than 40 neurodegenerative diseases that arise from lysosomal dysfunction evidence the importance of these organelles in maintaining cell health. Enzymatic deficiencies induce the deposition of abnormally processed materials believed to contribute to the characteristic mental retardation and brain damage. The fact that age-related diseases exhibit similar changes has prompted investigation of whether lysosomal dysfunction contributes to these neurodegenerative disorders. Post-mortem analyses have demonstrated evidence of such a contribution, since the presence of protein aggregates (e.g., neurofibrillary tangles and amyloid plaques in Alzheimer\u27s disease (AD) and huntingtin protein aggregates in Huntington\u27s Disease (HD)) has been correlated with evidence of lysosomal dysfunction. Although to a lesser degree, normal aging is associated with lysosomal disruption, thus establishing the “age” risk-factor in the two diseases. In vivo and in vitro models also report that experimentally-induced lysosomal dysfunction promotes abnormal protein processing. Moreover, protein aggregates and lysosomal dysfunction have been linked to synaptic deterioration and cognitive decline. However, there is a lack of mechanistic data to explain the numerous connections. The work presented here studied the effects of lysosomal perturbation in cultured hippocampal slices to understand why synapses are particularly vulnerable. A general lysosomal inhibitor was found to induce a distinct pathogenic cascade including, abnormal aggregation, protein fragmentation and microtubule destabilization. Subsequent changes included severe impairment of neuronal transport and corresponding declines in the expression of synaptic proteins. The application of a lysosomal modulator markedly up-regulated the levels of lysosomal enzymes, reversing the pathologic steps, thereby validating the identified cascade. Although smaller, lysosomal activation events have been found associated with neurodegenerative disorders and were speculated to represent a kind of compensatory response. In conclusion, the results described show that lysosomal dysfunction leads to the disruption of microtubule-based transport mechanisms vital for synaptic maintenance. They also indicate that lysosomal activation in AD and HD represents an internal repair system that (1) is activated in response to lysosomal disturbances and (2) can be pharmacologically enhanced as a potential avenue for therapeutic intervention to treat an array of neurodegenerative diseases.

Combined PIK3CA and FGFR Inhibition With Alpelisib and Infigratinib in Patients With PIK3CA-Mutant Solid Tumors, With or Without FGFR Alterations

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor–positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed