scholarly journals BCL2 inhibitors and MCL1 inhibitors for hematological malignancies

Blood ◽  
2021 ◽  
Author(s):  
Andrew W. Roberts ◽  
Andrew H Wei ◽  
David Ching Siang Huang
Keyword(s):  
Single Agent ◽  
Specific Inhibitor ◽  
Lymphocytic Leukemia ◽  
Tolerability Profile ◽  
Cell Of Origin ◽  
Apoptotic Pathway ◽  
Secondary Resistance ◽  
Bh3 Mimetics ◽  
Major Activity ◽  
Hematological Cancers

BCL2 and MCL1 are commonly expressed pro-survival (anti-apoptotic) proteins in hematological cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small molecule anti-cancer drugs, BH3-mimetics, now enable specific targeting of these proteins in patients. BH3-mimetics act by inhibiting the pro-survival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors which permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other anti-neoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia (CLL) and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3-mimetics are better suited to limited-duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3-mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several non-hematological tissues.

Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1563-1575 ◽  
Author(s):  
Roberto Alonso ◽  
Mónica López-Guerra ◽  
Ramanda Upshaw ◽  
Shanta Bantia ◽  
Caroline Smal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Investigation ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Apoptotic Pathway ◽  
Incurable Disease ◽  
Chemotherapeutic Approach ◽  
High Antitumor Activity

Abstract Chronic lymphocytic leukemia (CLL) is an incurable disease derived from the monoclonal expansion of CD5+ B lymphocytes. High expression levels of ZAP-70 or CD38 and deletions of 17p13 (TP53) and 11q22-q23 (ATM) are associated with poorer overall survival and shorter time to disease progression. DNA damage and p53 play a pivotal role in apoptosis induction in response to conventional chemotherapy, because deletions of ATM or p53 identify CLL patients with resistance to treatment. Forodesine is a transition-state inhibitor of the purine nucleoside phosphorylase with antileukemic activity. We show that forodesine is highly cytotoxic as single agent or in combination with bendamustine and rituximab in primary leukemic cells from CLL patients regardless of CD38/ZAP-70 expression and p53 or ATM deletion. Forodesine activates the mitochondrial apoptotic pathway by decreasing the levels of antiapoptotic MCL-1 protein and induction of proapoptotic BIM protein. Forodesine induces transcriptional up-regulation of p73, a p53-related protein able to overcome the resistance to apoptosis of CLL cells lacking functional p53. Remarkably, no differences in these apoptotic markers were observed based on p53 or ATM status. In conclusion, forodesine induces apoptosis of CLL cells bypassing the DNA-damage/ATM/p53 pathway and might represent a novel chemotherapeutic approach that deserves clinical investigation.

BCL-2 Phosphorylation Modulates Sensitivity to the BH3-Mimetic GX15-070 (Obatoclax) and Reduces Its Synergistic Interaction with Bortezomib in Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3464-3464 ◽  
Author(s):  
Patricia Perez Galan ◽  
Gael Roue ◽  
Monica Lopez Guerra ◽  
Neus Villamor ◽  
Emili Montserrat ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Primary Cells ◽  
Apoptotic Pathway ◽  
Bh3 Mimetic

Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries and is characterized by the accumulation of CD5-positive monoclonal B cells. This clonal excess of B cells is caused by a concomitant defect in both cell death and proliferation. A key factor that explains this inappropriate cell survival is the imbalanced expression of BCL-2 family proteins, thus representing an attractive therapeutic target for the treatment of this neoplasm. The current strategies for BCL-2 antagonism are based on small molecules that target several antiapoptotic BCL-2 proteins by mimicking a BH3 domain. Among them, GX15-070/Obatoclax (GeminX Biotechnologies) is pan-BCL-2 inhibitor that binds to BCL-2, BCL-W, BCL-XL and MCL-1 with high affinity, and has shown efficacy against several hematologic malignancies and solid tumors. In the present work, we report how GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells after short incubation times (3h), followed by the activation of the mitochondrial apoptotic pathway. Ex vivo experiments in CLL primary cells showed that GX15-070 as a single agent induces apoptosis at pharmacological concentrations. GX15-070 is also effective in CLL cells presenting alterations in P53, ATM, 13q deletions or high levels of ZAP-70 expression. LD50 at 20h were significantly higher in CLL cells (5.95 + 2.8 μM) compared to those previously reported in mantle cell lymphoma (MCL) primary cells (2.93 + 2.48 μM) (P<0.01). Of interest, these differences correlated with higher levels of pBCL-2(Ser70) in CLL compared to MCL primary cells. In the same context, we also demonstrated that ZAP-70+ CLL cases, which showed higher LD50 values than ZAP-70- ones, also expressed higher levels of pBCL-2(Ser70). Considering that BCL-2 phosphorylation at serine 70 residue is required for its antiapoptotic function, and that limits its interaction with proapoptotic multidomain and BH3-only proteins, it is conceivable that high levels of phosphorylated BCL-2 could impede or reduce GX15-070 activity. Both ERK1 (p44) and ERK2 (p42) kinases have been proposed to be responsible for BCL-2 phosphorylation. Considering these studies, we have demonstrated that pharmacological inhibition of MEK1/ERK pathway by PD98059 is able to reduce pBCL-2(Ser70) levels, increasing GX15-070 activity in CLL primary cells. In addition, as the protein phosphatase PP2A has been found to be responsible for BCL-2 dephosphorylation, its inhibition by okadaic acid increased pBCL-2(Ser70) levels, reducing GX15-070 cytotoxic activity. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of pBCL-2(Ser70), the degree of interaction between GX15-070 and bortezomib was also regulated by the levels of pBCL-2(Ser70). Accordingly, as ERK1/2 is responsible for this phosphorylation, we also demonstrated that ERK1/2 inhibition by PD98059 could reverse bortezomib-induced accumulation of pBCL-2(Ser70) and increased GX15-070 and bortezomib cytotoxic effect. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors.

scholarly journals The application of BH3 mimetics in myeloid leukemias

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Narissa Parry ◽  
Helen Wheadon ◽  
Mhairi Copland
Keyword(s):  
Specific Inhibitor ◽  
Standard Of Care ◽  
Mitochondrial Outer Membrane ◽  
Great Success ◽  
Intermembrane Space ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Bh3 Mimetics ◽  
Myeloid Leukemias ◽  
Need To Evaluate

AbstractExecution of the intrinsic apoptotic pathway is controlled by the BCL-2 proteins at the level of the mitochondrial outer membrane (MOM). This family of proteins consists of prosurvival (e.g., BCL-2, MCL-1) and proapoptotic (e.g., BIM, BAD, HRK) members, the functional balance of which dictates the activation of BAX and BAK. Once activated, BAX/BAK form pores in the MOM, resulting in cytochrome c release from the mitochondrial intermembrane space, leading to apoptosome formation, caspase activation, and cleavage of intracellular targets. This pathway is induced by cellular stress including DNA damage, cytokine and growth factor withdrawal, and chemotherapy/drug treatment. A well-documented defense of leukemia cells is to shift the balance of the BCL-2 family in favor of the prosurvival proteins to protect against such intra- and extracellular stimuli. Small molecule inhibitors targeting the prosurvival proteins, named ‘BH3 mimetics’, have come to the fore in recent years to treat hematological malignancies, both as single agents and in combination with standard-of-care therapies. The most significant example of these is the BCL-2-specific inhibitor venetoclax, given in combination with standard-of-care therapies with great success in AML in clinical trials. As the number and variety of available BH3 mimetics increases, and investigations into applying these novel inhibitors to treat myeloid leukemias continue apace the need to evaluate where we currently stand in this rapidly expanding field is clear.

scholarly journals Clinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent

2020 ◽  
Vol 11 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nur Syahidah Nor Hisam ◽  
Sze Ling Liew ◽  
Azizah Ugusman
Keyword(s):  
B Cell ◽  
Clinical Studies ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Apoptotic Pathway ◽  
Low Platelet Count ◽  
Apoptotic Proteins

B-cell lymphoma 2 (BCL-2) family proteins primarily work as a programmed cell death regulator, whereby multiple interactions between them determine cell survival. This explains the two major classes of BCL-2 proteins which are anti-apoptotic and pro-apoptotic proteins. The anti-apoptotic proteins are attractive targets for BCL-2 family inhibitors, which result in the augmentation of the intrinsic apoptotic pathway. BCL-2 family inhibitors have been studied extensively for novel targeted therapies in various cancer types, fibrotic diseases, aging-related as well as autoimmune diseases. Navitoclax is one of them and it has been discovered to have a high affinity toward BCL-2 anti-apoptotic proteins, including BCL-2, BCL-W and B-cell lymphoma-extra-large. Navitoclax has been demonstrated as a single agent or in combination with other drugs to successfully ameliorate tumor progression and fibrosis development. To date, navitoclax has entered phase I and phase II clinical studies. Navitoclax alone potently treats small cell lung cancer and acute lymphocytic leukemia, whilst in combination therapy for solid tumors, it enhances the therapeutic effect of other chemotherapeutic agents. A low platelet count has always associated with single navitoclax treatments, though this effect is tolerable. Moreover, the efficacy of navitoclax is determined by the expression of several BCL-2 family members. Here, we elucidate the complex mechanisms of navitoclax as a pro-apoptotic agent, and review the early and current clinical studies of navitoclax alone as well as with other drugs. Additionally, some suggestions on the development of navitoclax clinical studies are presented in the future prospects section.

scholarly journals Real Life Use of Bendamustine in Elderly Patients with Lymphoid Neoplasia

2021 ◽  
Vol 11 (4) ◽  
pp. 249
Author(s):  
Irene Dogliotti ◽  
Simone Ragaini ◽  
Francesco Vassallo ◽  
Elia Boccellato ◽  
Gabriele De Luca ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Rating Scale ◽  
Single Agent ◽  
Multivariable Analysis ◽  
Real Life ◽  
Lymphocytic Leukemia ◽  
Factors Affecting ◽  
Lymphoid Neoplasia ◽  
Baseline Factors ◽  
Grade 3

Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. Methods: An observational, retrospective study was carried out; patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. Results: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90–97%); after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses; the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis were sex, histological diagnosis, renal function, and planned bendamustine dose, while only type of lymphoma and bendamustine dose impacted on TTP. Main adverse events were neutropenia (grade ≥ 3: 43%) and infections (any grade: 36%), with 17% of patients requiring hospital admission. Conclusions: The responses to bendamustine, as well as survival, are relevant even in advanced age patients, with a manageable incidence of acute toxicity.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

scholarly journals Posttranslational Modification of Bcl-2 Facilitates Its Proteasome-Dependent Degradation: Molecular Characterization of the Involved Signaling Pathway

2000 ◽  
Vol 20 (5) ◽  
pp. 1886-1896 ◽  
Author(s):  
Kristin Breitschopf ◽  
Judith Haendeler ◽  
Philipp Malchow ◽  
Andreas M. Zeiher ◽  
Stefanie Dimmeler
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase ◽  
Map Kinase ◽  
Specific Inhibitor ◽  
26S Proteasome ◽  
Apoptotic Pathway ◽  
Critical Determinant ◽  
Intact Cells ◽  
Antiapoptotic Protein ◽  
Tnf Α

ABSTRACT The ratio of proapoptotic versus antiapoptotic Bcl-2 members is a critical determinant that plays a significant role in altering susceptibility to apoptosis. Therefore, a reduction of antiapoptotic protein levels in response to proximal signal transduction events may switch on the apoptotic pathway. In endothelial cells, tumor necrosis factor alpha (TNF-α) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein Bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate Bcl-2 degradation. Mutation of the consensus protein kinase B/Akt site or of potential protein kinase C or cyclic AMP-dependent protein kinase sites does not affect Bcl-2 stability. In contrast, inactivation of the three consensus mitogen-activated protein (MAP) kinase sites leads to a Bcl-2 protein that is ubiquitinated and subsequently degraded by the 26S proteasome. Inactivation of these sites within Bcl-2 revealed that dephosphorylation of Ser87 appears to play a major role. A Ser-to-Ala substitution at this position results in 50% degradation, whereas replacement of Thr74 with Ala leads to 25% degradation, as assessed by pulse-chase studies. We further demonstrated that incubation with TNF-α induces dephosphorylation of Ser87 of Bcl-2 in intact cells. Furthermore, MAP kinase triggers phosphorylation of Bcl-2, whereas a reduction in Bcl-2 phosphorylation was observed in the presence of MAP kinase-specific phosphatases or the MAP kinase-specific inhibitor PD98059. Moreover, we show that oxidative stress mediates TNF-α-stimulated proteolytic degradation of Bcl-2 by reducing MAP kinase activity. Taken together, these results demonstrate a direct protective role for Bcl-2 phosphorylation by MAP kinase against apoptotic challenges to endothelial cells and other cells.

Chromosomal aberrations in chronic lymphocytic leukemia detected by conventional cytogenetics with DSP30 as a single agent: Comparison with FISH

2011 ◽  
Vol 35 (8) ◽  
pp. 1032-1038 ◽  
Author(s):  
Aleksandra Kotkowska ◽  
Ewa Wawrzyniak ◽  
Jerzy Z. Blonski ◽  
Tadeusz Robak ◽  
Anna Korycka-Wolowiec
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Aberrations ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Conventional Cytogenetics

Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Hun Ju Lee ◽  
Michael Y. Choi ◽  
Tanya Siddiqi ◽  
Jacqueline Claudia Barrientos ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
Best Response ◽  
Car T ◽  
Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

CBIO-23. ANTIAPOPTOTIC Bcl-xL RESTRICTS APOPTOSIS IN SHH MEDULLOBLASTOMA AND PROMOTES PROGRESSION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi32
Author(s):  
Abigail Cleveland ◽  
Katherine Veleta ◽  
Timothy Gershon
Keyword(s):  
Therapeutic Potential ◽  
Radiation Sensitivity ◽  
Genetically Engineered ◽  
Translation Regulation ◽  
Spontaneous Apoptosis ◽  
Cell Of Origin ◽  
Tumor Resistance ◽  
Cerebellar Granule Neuron ◽  
Apoptotic Pathway

Abstract Medulloblastomas in most patients are distinctively sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Current treatments still fail 20%-60% of patients with SHH medulloblastoma and can leave survivors with long-term neurocognitive and social deficits. Understanding the mechanisms driving the typical radiation-sensitivity may identify less-toxic therapeutic strategies and provide insight into treatment failure. We previously showed that radiation sensitivity depends on the intrinsic apoptotic pathway, mediated by pro-apoptotic BAX. In cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH medulloblastoma, BAX activity is directly inhibited by anti-apoptotic BCL-xL; Bcl-xL-deleted CGNPs undergo spontaneous apoptosis. To test the therapeutic potential of disrupting BCL-xL in medulloblastoma, we conditionally deleted Bcl-xL in mice genetically engineered to develop SHH medulloblastoma. Here, I show that Bcl-xL deletion slows SHH medulloblastoma growth and prolongs survival of medulloblastoma-bearing mice. Bcl-xL-deleted tumors initially showed increased rates of spontaneous apoptosis, but this effect waned over time, suggesting the emergence of BCL-xL-independent survival mechanisms. We also noted increased microglial infiltration in Bcl-xL-deleted medulloblastomas. We hypothesize that IGF1 produced by microglia in the tumor microenvironment may be contributing to tumor resistance by upregulating translation of MCL-1, an anti-apoptotic BCL-xL homolog. IGF1 is known to upregulate translation through the mTOR pathway, while anti-apoptotic MCL-1 protein abundance is dependent upon translation regulation. Our on-going studies are testing the efficacy of pharmacologically targeting BCL-xL in mice with medulloblastoma, in combination with targeting IGF1 signaling using mTORC1 inhibitors.

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