ZIA BC 011780 (ZIA) | |||
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Title | Clinical development of mechanism-based lymphoma therapies | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Staudt, Louis | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $764,274 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) | Non Hodgkins Lymphoma (100.0%) | ||
Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
To identify synergistic drug combinations, we work with Craig Thomas at NCATS on matrix drug screens, which use acoustic dispensing robots to array two drugs in a dose titration series against one another, looking for doses at which the drugs achieve greater cell killing together than individually. We use a chemical library of >2000 drugs that are either approved or in development as cancer therapeutics plus small molecules that serve as tool compounds for important signaling and regulatory pathways, such as NF-kB. In the initial screen using ABC DLBCL lines, we searched for compounds that would synergize or antagonize the toxicity of ibrutinib. Multiple agents targeting the PI(3) kinase pathway strongly synergized with ibrutinib, including drugs targeting the PI(3) kinase catalytic subunit, Akt, or mTORC1. This result is consistent with the notion that ibrutinib primarily targets the pro-survival NF-kB pathway, while having less effect on the PI(3) kinase survival pathway, which is also engaged by BCR signaling. Ibrutinib synergized strongly with PRT-060318, an inhibitor of the SYK tyrosine kinase that is activated proximally in the BCR pathway, and with ABT-199, a BCL2 inhibitor that we have studied extensively in the context of ibrutinib resistance. Another broad class of synergistic compounds included cancer chemotherapeutic agents that elicit a DNA damage response or trigger apoptosis by interfering with microtubules. The reasons behind this synergism is likely due to the ability of NF-kB to antagonize the apoptotic effects of chemotherapy. Indeed, all components of both the CHOP and EPOCH chemotherapy regimens synergized with ibrutinib in killing ABC DLBCL cells, providing impetus to combine ibrutinib with these regimens. Based on our identification of chronic active BCR signaling as a key survival pathway in ABC DLBCL, we conducted a phase I/II clinical trial of ibrutinib using gene expression profiling to assign patients to the ABC and GCB subtypes of DLBCL. As predicted by our laboratory investigations, ibrutinib produced a 37% response rate in ABC DLBCL patients but only a 5% response rate in GCB DLBCL, demonstrating that the molecular diagnosis of DLBCL subtypes can inform precision medicine trials. This translated into improved overall survival in ABC relative to GCB DLBCL, including several patients who have remained in complete remission for more than 3-6 years, taking ibrutinib daily without discernable side effects. Based on these promising results, ibrutinib plus chemotherapy is now being evaluated in untreated non-GCB DLBCL patients in a phase 3 randomized trial being conducted by Jannsen. This trial used an immunohistochemical test we developed with our LLMPP colleagues to identify patients with non-GCB DLBCL and is the first phase 3 trial in DLBCL to use molecular profiling for enrollment. This trial has enrolled >800 patients and will read out in 2018. To understand the molecular basis for response to ibrutinib within ABC DLBCL, we resequenced the tumors for recurrent oncogenic mutations. Tumors with CD79B mutations responded more frequently than those with wild type CD79B (55% vs 30%), demonstrating the clinical validity of our observation that these mutations augment BCR signaling. Nonetheless, the majority of responding patients on this trial had wild type CD79B, which is in keeping with our demonstration that chronic active BCR signaling is driven by self-antigen reactivity of the immunoglobulin variable regions. Notably, tumors that had both a CD79B mutation and a MYD88 L265P mutation responded frequently (80%), whereas those with only a MYD88 mutation did not respond. This ""double mutant"" genotype occurred in more ABC tumors (11%) than expected by chance based on the prevalence of each mutation individually, providing genetic evidence that the MYD88 and BCR pathways cooperate in these tumors. We showed that ABC cell lines with the double mutant genotype responded to ibrutinib, whereas ABC lines with |