BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Fiskus, Warren; Mill, Christopher; Perera, Dimuthu; Birdwell, Christine; Deng, Qing; Yang, Haopeng; Lara, Bernardo H; Jain, Nitin; Burger, Jan A.; Ferrajoli, Alessandra; Davis, John A.; Saenz, Dyana T.; Jin, Wendy; Coarfa, Cristian; Crews, Craig M.; Green, Michael R.; Khoury, Joseph D.; Bhalla, Kapil N.

doi:10.1038/s41375-021-01181-w

Cited by 20 publications

(28 citation statements)

References 54 publications

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“…Data on three newly established PDX models of RT-DLBCLs were recently published, namely, clonally-related and clonally-unrelated RT ( 122 ). These PDX models display protein expression of IRF4, TCF4, and BCL2.…”

Section: Future Perspectivesmentioning

confidence: 99%

Biology and Treatment of Richter Transformation

Condoluci

Rossi

2022

Front. Oncol.

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Richter transformation (RT), defined as the development of an aggressive lymphoma on a background of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), represents a clinical unmet need because of its dismal prognosis. An increasing body of knowledge in the field of RT is arising from the recent development of preclinical models depicting the biology underlying this aggressive disease. Consistently, new therapeutic strategies based on a genetic rationale are exploring actionable pathogenic pathways to improve the outcome of patients in this setting. In this review, we summarize the current understandings on RT biology and the available treatment options.

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Section: Future Perspectivesmentioning

confidence: 99%

Biology and Treatment of Richter Transformation

Condoluci

Rossi

2022

Front. Oncol.

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“…The molecular mechanism beneath this effect relies on the concomitant inactivation of Mcl-1, c-Myc, and Bcl-2, via GSK3β activation [85]. Similar results were obtained combining venetoclax with other BH3 mimetics or with bromodomain extra-terminal (BET) protein targeting chimera (PROTAC), bifunctional molecules capable of hijacking the ubiquitin-proteasome system to induce degradation of BET proteins [103], suggesting that the simultaneous targeting of key molecular players within RS cells may represents a winning strategy [104].…”

Section: Combination Strategiesmentioning

confidence: 61%

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Iannello

Deaglio

Vaisitti

2022

Curr. Treat. Options in Oncol.

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Opinion statementIn the last 10–15 years, the way to treat cancers has dramatically changed towards precision medicine approaches. These treatment options are mainly based on selective targeting against signaling pathways critical for or detrimentally activated in cancer cells in cancer cells, as well as exploiting molecules that are specifically expressed on neoplastic cells, also known as tumor-associated antigens. These considerations hold true also in the hematological field where a plethora of novel targeted agents have reached patients’ bedside, significantly improving clinical responses. Chronic lymphocytic leukemia (CLL) is an example of how targeted therapies, such as BTK, PI3K, or Bcl-2 inhibitors as well as anti-CD20 antibodies, have improved patients’ management, even when adopted as frontline treatment. However, these advancements do not apply to Richter’s syndrome (RS), the transformation of CLL into a very aggressive and fatal lymphoma, occurring in 2–10% of patients. RS is usually a fast-growing lymphoma of the diffuse large B cell or the Hodgkin’s variant, with a dismal prognosis. Despite advancements in depicting and understanding the genetic background of RS and its pathogenesis, no significant clinical results have been registered. In the last couple of years, several studies have started to investigate the impact of novel drugs or drug combinations and some of them have opened for clinical trials, currently in phase I or II, whose results will be soon available. This review will present an overview of current and most recent therapeutic options in RS, discussing also how results coming from xenograft models may help in designing and identifying novel treatment opportunities to overcome the lack of effective therapies.

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“…Despite the remarkable preclinical activity of BET inhibitors in hematological malignancies, studies to identify beneficial combination therapy approaches to enhance efficacy have been reported [31]. As expected, synergism was observed when combining BET inhibitors (e.g., BAY 1238097, GS-5829, OTX015) with inhibitors of BTK (ibrutinib), SYK (entospletinib), PI3K (copanlisib, idelalisib), or BCL2 (venetoclax) in preclinical models of CLL [32-34] and DLBCL-RT [35]. Interestingly, the anti-leukemic activity of BET inhibitor, GS-5829, proved to be synergistic in combination with ibrutinib or idelalisib in primary CLL / nurse-like cell co-cultures reflective of the LN TME in CLL [32].…”

Section: Introductionmentioning

confidence: 90%

A novel triple-action inhibitor targeting B-cell receptor signaling and BRD4 demonstrates preclinical activity in chronic lymphocytic leukemia

Smith

Eiken

Moore

et al. 2022

Preprint

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B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival-signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL still remains an incurable disease due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination therapy-related toxicities. Using SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, we demonstrate that SRX3305 attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits activation-induced proliferation of primary CLL cells in vitro, and effectively blocks microenvironment-mediated survival signals including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL providing significant rationale for its development as a therapeutic agent for CLL and related disorders.

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BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Cited by 20 publications

References 54 publications

Biology and Treatment of Richter Transformation

Biology and Treatment of Richter Transformation

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

A novel triple-action inhibitor targeting B-cell receptor signaling and BRD4 demonstrates preclinical activity in chronic lymphocytic leukemia

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