Jonathan H. Schatz

A targeted mutational landscape of angioimmunoblastic T-cell lymphoma

The genetics of angioimmunoblastic T-cell lymphoma (AITL) are very poorly understood. We defined the mutational landscape of AITL across 219 genes in 85 cases from the United States and Europe. We identified ≥2 mutations in 34 genes, nearly all of which were not previously implicated in AITL. These included loss-of-function mutations in TP53 (n = 4), ETV6 (n = 3), CCND3 (n = 2), and EP300 (n = 5), as well as gain-of-function mutations in JAK2 (n = 2) and STAT3 (n = 4). TET2 was mutated in 65 (76%) AITLs, including 43 that harbored 2 or 3 TET2 mutations. DNMT3A mutations occurred in 28 (33%) AITLs; 100% of these also harbored TET2 mutations (P < .0001). Seventeen AITLs harbored IDH2 R172 substitutions, including 15 with TET2 mutations. In summary, AITL is characterized by high frequencies of overlapping mutations in epigenetic modifiers and targetable mutations in a subset of cases.

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential.

Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1

Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning antiapoptotic proteins BCL2 and MCL1 are frequently expressed. Here we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find that clinical samples have frequent co-expression of MCL1 and BCL2, suggesting that therapeutic strategies targeting only one will lead to treatment failures owing to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest antitumor activity against most DLBCL lines and resulted in compensatory upregulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent antitumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.

Targeting the PI3K/AKT/mTOR Pathway in Non-Hodgkin’s Lymphoma: Results, Biology, and Development Strategies

Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in non-Hodgkin’s lymphoma (NHL), prompting evaluation of the rapamycin-analog (rapalog) mTOR inhibitors in multiple clinical trials. The drugs show activity as single agents, and the rapalog temsirolimus is now accepted as a therapeutic option in relapsed/refractory mantle cell lymphoma. Response rates, however, are typically below 50%, resulting in remissions that are neither complete nor durable. Results of preclinical studies shed important new light on resistance mechanisms that may explain results. Looking ahead, it is likely PI3K/AKT/mTOR inhibition will find expanded roles in NHL therapy due to 1) assessments of the rapalogs in combination with other therapies and in less heavily pretreated patients, 2) the development and evaluation of multiple novel inhibitors of the pathway that may increase specificity and potency, 3) alternative treatment strategies able to bypass particular resistance mechanisms, and 4) increased efforts to identify biomarkers for better pretreatment patient stratification.

Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis

Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis

Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy

CDK4 activation/RB phosphorylation occurs in 50% of indolent but high-risk follicular lymphomas and implies susceptibility to dual CDK4 and BCL2 inhibition.

Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors.

The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and ∼70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK(+) NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ∼10 months. Kinase domain mutations are detectable in 25% to 37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications.

Mouse models of cancer as biological filters for complex genomic data

Genetically and pathologically accurate mouse models of leukemia and lymphoma have been developed in recent years. Adoptive transfer of genetically modified hematopoietic progenitor cells enables rapid and highly controlled gain- and loss-of-function studies for these types of cancer. In this Commentary, we discuss how these highly versatile experimental approaches can be used as biological filters to pinpoint transformation-relevant activities from complex cancer genome data. We anticipate that the functional identification of genetic ‘drivers’ using mouse models of leukemia and lymphoma will facilitate the development of molecular diagnostics and mechanism-based therapies for patients that suffer from these diseases.

Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447

The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type proteins ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases.

Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?

Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process.