A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl).

BACKGROUND: Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients. METHODS: URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC-rearranged round cell sarcomas, (2) BCOR::CCNB3-rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed. RESULTS: In total, 148 patients were identified [88/148 (60%) CIC-rearranged sarcoma (median age 32 years, range 7-78), 33/148 (22%) BCOR::CCNB3-rearranged (median age 17 years, range 5-91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4-70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5-98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7-51.3) in CIC-rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1-90.6; p < 0.0001). CONCLUSIONS: This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype.

Demographics, Outcomes, and Risk Factors for Patients with Sarcoma and COVID-19: A CCC19-Registry Based Retrospective Cohort Study.

BACKGROUND: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19. METHODS: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed. RESULTS: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity. CONCLUSIONS: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

Safe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp.

Immunotherapies directed at T-cell activation through antibodies targeting checkpoint proteins, such as programmed cell death 1 (PD1), are rapidly becoming the new standard of care in the treatment of several malignancies. Cemiplimab is a monoclonal antibody targeting PD1 that has recently emerged as a highly active treatment for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC). Patients who have received an organ transplant (OTRs) have been traditionally excluded from clinical trials with checkpoint inhibitors (CIs), given concerns for organ rejection. Renal transplant recipients (RTRs) are more likely to develop cancers than the general population, and skin cancers are among the most frequent malignancies. We report the case of a 72-year-old man with a history of a kidney transplant who presented with a rapidly growing, locally advanced squamous cell carcinoma (SCC) of the scalp that recurred within four weeks from surgical resection. The patient was able to safely receive ten cycles of cemiplimab so far with significant clinical benefit, and no issues with his kidney function, while continuing immunosuppression with low dose prednisone alone. An ongoing clinical trial (NCT04339062) is further exploring the safety of CIs in patients with metastatic CSCC who have previously received allogeneic hematopoietic stem cell transplant or a kidney transplant.

Modern Management of High-risk Soft Tissue Sarcoma With Neoadjuvant Chemoradiation: A Single-center Experience.

OBJECTIVE: Neoadjuvant chemoradiation (NA-CRT), followed by resection of high-risk soft tissue sarcoma (STS), may offer good disease control and toxicity outcomes. We report on a single institution's modern NA-CRT experience. MATERIALS AND METHODS: Delay to surgical resection, resection margin status, extent of necrosis, tumor cell viability, presence of hyalinization, positron emission tomography (PET)/computed tomography data, and treatment toxicities were collected. Using the Kaplan-Meier survival analysis, 5-year overall survival, disease-free survival, distant metastasis-free survival, and local control (LC) were estimated. Clinicopathologic features and PET/computed tomography avidity changes were assessed for their potential predictive impact using the log-rank test. RESULTS: From 2011 to 2018, 37 consecutive cases of localized high-risk STS were identified. Twenty-nine patients underwent ifosfamide-based NA-CRT to a median dose of 50 Gy before en bloc resection. At a median follow-up of 40.3 months, estimated 5-year overall survival was 86.1%, disease-free survival 70.2%, distant metastasis-free survival 75.2%, and LC 86.7%. Following NA-CRT, a median reduction of 54.7% was observed in tumor PET avidity; once resected, median tumor necrosis of 60.0% with no viable tumor cells was detected in 13.8% of the cases. Posttreatment resection margins were negative in all patients, with 27.6% having a margin of ≤1 mm. Delays of over 6 weeks following the end of radiation treatment to surgical resection occurred in 20.7% cases and was suggestive of inferior LC (92.8% vs. 68.6%, P=0.025). CONCLUSIONS: This single-institution series of NA-CRT demonstrates favorable disease control. Delay in surgical resection was associated with inferior LC, a finding that deserves further evaluation in a larger cohort. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Diagnosis, Prognosis, and Treatment of Alveolar Soft-Part Sarcoma: A Review.

Importance: Alveolar soft-part sarcoma (ASPS) is a rare, translocation-driven sarcoma of the soft tissues. Alveolar soft-part sarcoma often affects young adults and is characterized by indolent behavior but early evidence of metastatic spread. After recognition of ASPS as a specific entity in 1952, retrospective data indicated prolonged survival in patients with metastases, despite inherent resistance to conventional doxorubicin-based chemotherapy. Tyrosine kinase inhibitors and immune checkpoint inhibitors have provided unexpected new treatment strategies for ASPS. Observations: This review includes articles published between 1952 and March 1, 2018. With the introduction of new molecular diagnostic tools and therapies, the distinctive features of ASPS have become more evident. The identification and better understanding of molecular pathways activated by the characteristic t(X;17)(p11;q25) translocation and its correspondent chimeric ASPSCR1-transcription factor E3 (TFE3) fusion protein open new paths to drug development. The associations of TFE3 and facilitation of an immunosuppressive microenvironment provide a rationale for exploring treatments that affect the balance between T-effector cells and T-regulatory cells. Tyrosine kinase inhibitors, such as sunitinib, cediranib, and pazopanib, show activity with either tumor responses or disease stabilization in more than 50% of the cases. Given the association of new agents with patient outcomes, it is too early to say whether metastatic ASPS should still be considered incurable in all patients. Conclusions and Relevance: The biologic outcomes of the canonical genomic event in ASPS remain under investigation; a better understanding of the tumor microenvironment and the multiple pathways activated in this sarcoma, including unusual bioenergetics, MET signaling, and angiogenesis, should lead to more rational therapy. Basket trials and related prospective studies focusing on the intersection of specific signaling pathways and diseases with unique genomic features, such as ASPS, will provide an understanding of new options for care.

Extraskeletal myxoid chondrosarcoma with massive pulmonary metastases.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant mesenchymal neoplasm of uncertain differentiation characterized by rearrangements of the NR4A3 gene. EMC often affects adults around the age of 50 and arise in the deep tissues of the proximal extremities and limb girdles. EMC is characterized by indolent growth rate but strong tendency to local recurrence and metastatic spread. No systemic treatment is specifically approved by the FDA for this disease and surgery has been traditionally the only potentially curative strategy. CASE PRESENTATION: A 41-year-old Caucasian woman originally presented with a 14.8 cm left thigh mass. She was managed with wide local resection but after 2 years she developed recurrent disease in the pelvis and in the lungs; the lung involvement was characterized by innumerable nodules without any significant respiratory symptoms. After failing three clinical trials, she experienced prolonged disease control while on treatment with the tyrosine kinase inhibitor (TKI) pazopanib and radiation therapy delivered to the pelvic lesion. Dose reduction of pazopanib due to severe diarrhea was followed by rapid disease progression in the pelvis requiring vascular stenting; increase in tumor growth after discontinuation of a TKI has been described in other malignancies and is a possibility in this specific patient. CONCLUSION: While surgical management of EMC with or without radiation therapy is still the preferable approach when feasible, small series support the use of tyrosine kinase inhibitors and possible new immunotherapies in selected patients. Basket trials focusing on diseases with unique genomic features such as EMC will hopefully provide a better understanding of new options for care.

BET and BRAF inhibitors act synergistically against BRAF-mutant melanoma.

Despite major advances in the treatment of metastatic melanoma, treatment failure is still inevitable in most cases. Manipulation of key epigenetic regulators, including inhibition of Bromodomain and extra-terminal domain (BET) family members impairs cell proliferation in vitro and tumor growth in vivo in different cancers, including melanoma. Here, we investigated the effect of combining the BET inhibitor JQ1 with the BRAF inhibitor Vemurafenib in in vitro and in vivo models of BRAF-mutant melanoma. We performed cytotoxicity and apoptosis assays, and a xenograft mouse model to determine the in vitro and in vivo efficacy of JQ1 in combination with Vemurafenib against BRAF-mutant melanoma cell lines. Further, to investigate the molecular mechanisms underlying the effects of combined treatment, we conducted antibody arrays of in vitro drug-treated cell lines and RNA sequencing of drug-treated xenograft tumors. The combination of JQ1 and Vemurafenib acted synergistically in BRAF-mutant cell lines, resulting in marked apoptosis in vitro, with upregulation of proapoptotic proteins. In vivo, combination treatment suppressed tumor growth and significantly improved survival compared to either drug alone. RNA sequencing of tumor tissues revealed almost four thousand genes that were uniquely modulated by the combination, with several anti-apoptotic genes significantly down-regulated. Collectively, our data provide a rationale for combined BET and BRAF inhibition as a novel strategy for the treatment of melanoma.

The novel kinesin spindle protein (KSP) inhibitor SB-743921 exhibits marked activity in in vivo and in vitro models of aggressive large B-cell lymphoma.

The kinesin spindle protein (KSP) is a mitotic protein essential for cell cycle control and motility. SB-743921 (hereafter SB-921) is an inhibitor that selectively targets the ATP-binding domain of the KSP. The preclinical activity of SB-921 was evaluated in models of diffuse large B-cell lymphoma (DLBCL). The cytotoxicity of SB-921 was evaluated in a series of germinal center (GC-DLBCL) and post-germinal center (ABC-DLBCL) DLBCL cell lines and a murine lymphoma xenograft model. GC-DLBCL lines generally demonstrated greater sensitivity to SB-921. IC50 values ranged between 1 nM and 900 nM for GC-DLBCL compared to 1 nM to 10 µM for ABC lines. SB-921 demonstrated marked activity in a xenograft model of Ly-1 (GC-DLBCL). While SB-921 was relatively more active in GC derived cell lines, ABC-derived lines still underwent apoptosis at higher concentrations. These results demonstrate that SB-921 inhibits proliferation and induces apoptosis in both GC-DLBCL and ABC-DLBCL.

Development and characterization of a novel CD19CherryLuciferase (CD19CL) transgenic mouse for the preclinical study of B-cell lymphomas.

PURPOSE: To generate a transgenic mouse that when crossed with spontaneous mouse models of lymphoma will allow for quantitative in vivo measurement of tumor burden over the entire spectrum of the disease and or response to therapy in a "disease" or lymphoma subtype-specific manner. EXPERIMENTAL DESIGN: We developed a novel genetically engineered transgenic mouse using a CherryLuciferase fusion gene targeted to the CD19 locus to achieve B-cell-restricted fluorescent bioluminescent emission in transgenic mouse models of living mice. The use of a dual function protein enables one to link the in vivo analysis via bioluminescence imaging to cell discriminating ex vivo analyses via fluorescence emission. RESULTS: The spatiotemporal tracking of B-cell lymphoma growth and the response of an established B-cell lymphoma to a drug known to induce remission was evaluated in a double transgenic animal obtained by crossing the CD19CherryLuciferase transgenic mouse to a mouse model of an aggressive B-cell lymphoma. The observations validated the use of the CD19CherryLuciferase transgenic mouse in the assessment of an active drug routinely used in the treatment of lymphoproliferative malignancies. CONCLUSIONS: The transgenic mouse described here is the first of its kind, intended to be used to hasten translational studies of novel agents in lymphoma, with the intent that understanding the relevant pharmacology before clinical study will accelerate successful development in clinical studies.

Targeting survival pathways in lymphoma.

Targeting cellular death pathways including apoptosis is a promising strategy for cancer drug discovery. To date at least three major types of cell death have been distinguished, including: apoptosis, autophagy, and necrosis. Increasing evidence has begun to support a role of Bcl-2-family members in the cellular pathways involved in each of these processes. The induction of apoptosis in different types of tissue and in response to various stressors is a complex process that is controlled by different BCL-2 family members. Pharmacologic modulation of BCL-2 proteins and apoptosis can be achieved through different ways including the use of: (1) Modified peptides; (2) Small molecule inhibitors ofanti-apoptotic proteins; (3) Antisense strategies; and (4) TRAIL targeting. Non-peptide based small-molecule inhibitors of signaling pathways are at present the strategy of choice given their low antigenicity and generally more favorable pharmacokinetic and pharmacodynamic features, especially as they pertain to volume of distribution and intracellular accumulation. Bcl2-family inhibitors are showing impressive preclinical efficacy in animal models and are moving rapidly towards phase I and II clinical trials. Appropriate preclinical studies will need to identify the optimal strategies for combining these agents, with an emphasis on the importance of dose and schedule dependency.

Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies.

PURPOSE: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma. EXPERIMENTAL DESIGN: Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies. RESULTS: In vitro, pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone. CONCLUSION: Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies.

Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma.

PURPOSE: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1. EXPERIMENTAL DESIGN: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL. RESULTS: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-X(L), and an increase in accumulation of acetylated histone H3, acetylated alpha-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone. CONCLUSIONS: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.

Bortezomib-induced tumor lysis syndrome in a patient with HIV-negative plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma classified by the World Health Organization as a subtype of diffuse large B-cell lymphoma that shares many morphologic and immunophenotypic features with multiple myeloma. It is extremely rare in immunocompetent patients. Because of the small number of patients reported, this rare lymphoma remains a poorly characterized and understood entity with presently no standard recommendations regarding the optimal treatment. Herein, we report a dramatic clinical response coupled with tumor lysis syndrome to a bortezomib-based treatment in an HIV-negative patient with refractory plasmablastic lymphoma.

The anti-histaminic cyproheptadine synergizes the antineoplastic activity of bortezomib in mantle cell lymphoma through its effects as a histone deacetylase inhibitor.

Cyproheptadine, an inhibitor of the H1 histamine receptors, has recently shown activity in models of leukaemia and myeloma, presumably through inhibition of cyclin-D expression. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin-D1. We investigated the effect of cyproheptadine alone and in combination with the proteasome inhibitor bortezomib in models of MCL. The combination of these drugs was mathematically synergistic, producing significant reductions in the mitochondrial membrane potential leading to apoptosis. In a severe combined immunodeficient beige mouse model, cyproheptadine plus bortezomib demonstrated a statistically significant advantage compared to either agent alone.

New drugs for the treatment of lymphoma.

Historically, most drugs developed for treatment of leukemias, lymphomas, and myeloma had already been studied in the solid tumor setting. Nearly 10 years ago, chronic myelogenous leukemia (CML) forever changed this paradigm. Imatinib showed that it was possible to nullify the pathognomic genetic lesion in a hematologic malignancy. Since the approval of imatinib for CML, a host of new drugs active in blood cancers have emerged. This article highlights some areas of innovative drug development in lymphoma where possible; it emphasizes the biologic basis for the approach, linking this essential biology to the biochemical pharmacology. The article focuses on the many new targets including Syk, Bcl-2, CD-40, and the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin pathway.

Regenerating articular tissue by converging technologies.

Scaffolds for osteochondral tissue engineering should provide mechanical stability, while offering specific signals for chondral and bone regeneration with a completely interconnected porous network for cell migration, attachment, and proliferation. Composites of polymers and ceramics are often considered to satisfy these requirements. As such methods largely rely on interfacial bonding between the ceramic and polymer phase, they may often compromise the use of the interface as an instrument to direct cell fate. Alternatively, here, we have designed hybrid 3D scaffolds using a novel concept based on biomaterial assembly, thereby omitting the drawbacks of interfacial bonding. Rapid prototyped ceramic particles were integrated into the pores of polymeric 3D fiber-deposited (3DF) matrices and infused with demineralized bone matrix (DBM) to obtain constructs that display the mechanical robustness of ceramics and the flexibility of polymers, mimicking bone tissue properties. Ostechondral scaffolds were then fabricated by directly depositing a 3DF structure optimized for cartilage regeneration adjacent to the bone scaffold. Stem cell seeded scaffolds regenerated both cartilage and bone in vivo.

The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies.

Overexpression of antiapoptotic members of the Bcl-2 family is observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying the antiapoptotic influence of these proteins can potentially overcome this resistance, and may complement conventional chemotherapy. ABT-737 is a BH3-only mimetic and potent inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-X(L), and Bcl-w. In vitro, ABT-737 exhibited concentration-dependent cytotoxicity against a broad panel of lymphoma cell lines including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). ABT-737 showed synergism when combined with the proteasome inhibitors bortezomib or carfilzomib in select lymphoma cell lines and induced potent mitochondrial membrane depolarization and apoptosis when combined with either. ABT-737 plus bortezomib also induced significant apoptosis in primary samples of MCL, DLBCL, and chronic lymphocytic leukemia (CLL) but no significant cytotoxic effect was observed in peripheral blood mononuclear cells from healthy donors. In severe combined immunodeficient beige mouse models of MCL, the addition of ABT-737 to bortezomib enhanced efficacy compared with either drug alone and with the control. Collectively, these data suggest that ABT-737 alone or in combination with a proteasome inhibitor represents a novel and potentially important platform for the treatment of B-cell malignancies.

Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma.

Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.

Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas.

Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.