BCL-2 Emerges as an Attractive Target in Solid and Hematologic Cancers

Publication
Article
Oncology Live®Vol. 20/No.5
Volume 20
Issue 5

Based on the crucial role of BCL-2 family proteins in apoptosis regulation, targeting these proteins using BCL-2 inhibitors offers a potentially new therapeutic option for patients with various types of hematologic malignancies and, more recently, patients with solid tumors.

The gene encoding B-cell lymphoma-2 (BCL-2) was identified more than 30 years ago in a patient with follicular lymphoma (FL) who had a chromosomal translocation that led to dysregulated BCL-2 expression.1 When the BCL-2 gene product was reported to block cell death instead of enhancing cell proliferation, which was the expected action of oncogenes, the link among BCL-2, apoptosis, and cancer was established.2,3 This finding led to the idea that impaired apoptosis was an important feature required for tumorigenesis.4

High BCL-2 expression levels discovered in hematologic malignancies have led to numerous clinical investigations, paving the way for the initial approval in chronic lymphocytic leukemia (CLL) for venetoclax (Venclexta), the first BCL-2 inhibitor indicated for cancer treatment, in 2016.5 Additional investigations of venetoclax are ongoing in hematologic malignances, and new drugs are in development. Meanwhile, investigators are hoping to develop BCL-2 as an actionable target in solid tumors, with recent findings in venetoclax studies providing potential support for these investigations.

Role of BCL-2 in Cancer

However, there are challenges for targeting BCL-2 in both hematologic and solid tumors. Resistance to BH3 mimetics that target BCL-2 and BCL-2/BCL-XL has been observed in vitro and in vivo.6-8 There are also altered cellular activities that have not been eliminated via BCL-2 protein targeting. In models of γ-irradiation—induced thymic lymphoma, overexpression of BCL-2, which is usually considered to be a procancer event, protects against the development of tumors.9 It is unclear at this time whether these concerns will remain in clinical trials; however, promising study results support the potential of BH3 mimetics to dramatically improve survival in patients with various cancer types.The BCL-2 family proteins are important for regulation of cell death at both the mitochondria and the endoplasmic reticulum. The proteins function to regulate mitochondrial outer membrane permeabilization through a coordinated series of protein—protein and protein–membrane interactions that are associated with protein conformational changes that control pore formation in organelle membranes.10,11 When BCL-2 is overexpressed, it blocks BAX, an apoptotic protein, and prevents mitochondrial pore formation and inhibits the release of cytochrome C, which leads to inhibited or reduced cell death.12

To maintain proliferation of cancer cells, tumors must prevent apoptosis and are reliant on BCL-2 proteins to block cell death under environmental pressure from the immune system or chemotherapeutic agents. In these conditions, tumors have been said to be “BCL-2 addicted” and more susceptible to BCL-2 inhibitors.13 Hematologic cancers generally are more dependent on BCL-2, whereas solid tumors have been reported to be more dependent on other antiapoptotic proteins, including BCL-XL or MCL-1.14 Therefore, selective antagonism of BCL-2 family proteins provides an opportunity to treat tumors.

BCL-2 Expression in Cancers

Figure 2. BCL-2 Expression in Selected Cancer Types

Efforts to Target BCL-2

The BCL-2 family proteins are classified based on structure and BCL-2 homology (BH) domains. There are 4 BH domains, BH1 to BH4, present in the antiapoptotic members (BCL-2, BCL-XL, BCL-W, MCL-1, and A1/BFL-1). These domains contain a hydrophobic groove that binds to the BH3 domain found in the proapoptotic proteins (BAX, BAK, and BOK) that contain BH1 to BH3.15 Another group of BCL-2 family proteins only contains the BH3 domain, including the proapoptotic activators BID and BIM and the proapoptotic sensitizers BAD, BIK, BMF, HRK, NOXA, and PUMA (Figure 1). BH3 mimetics have been developed to mimic the action of certain proteins that only contain the BH3 domain, resulting in inhibition of antiapoptotic BCL-2 family proteins and apoptosis promotion in cancer.The majority of patients with CLL overexpress BCL-2.16 Increased BCL-2 expression is also found in most patients with acute lymphocytic leukemia and is frequently reported in acute myeloid leukemia (AML).17,18 Approximately 90% of patients with FL harbor a chromosomal translocation that is thought to cause BCL-2 overexpression.19 Relatively high BCL-2 expression also has been reported in over 40% of patients with diffuse large B-cell lymphoma (DLBCL).20 Altered BCL-2 expression has been reported in various solid tumor types, including prostate (30%-60% at diagnosis, nearly 100% of hormone-refractory cases), breast (75%), small cell lung cancer (SCLC; >90%), and non— small cell lung cancer (50%).21-24 Additionally, increased BCL-2 expression has been reported in ovarian, bladder, colorectal (60%), neuroblastoma, and some head and neck cancers (17%).25-29 (Figure 2).Venetoclax, formerly known as ABT-199, is an orally available inhibitor that has 100-fold greater affinity for BCL-2 than BCL-XL.30 No thrombocytopenia has been reported with this inhibitor due to its high affinity for BCL-2 and low binding to BCL-XL. However, treatment led to tumor lysis syndrome in some patients because of its potent BCL-2 inhibition, requiring development of a dose-escalation strategy and close surveillance of patients.31 An 80% response rate and manageable adverse effects (AEs) were reported in patients with relapsed CLL or small lymphocytic leukemia (SLL).

Single-agent venetoclax was the first BH3 mimetic that the FDA approved for cancer treatment, with an indication for use after at least 1 prior therapy in patients with CLL and 17p chromosomal deletion (del17p), which is a biomarker for TP53 loss and poor prognosis.31-33 The label subsequently was expanded to include CLL/SLL with or without del17p. Additionally, it is now indicated in combination with azacytidine, decitabine, or low-dose cytarabine for treating newly diagnosed AML in adults 75 years or older or those who have comorbidities that preclude the use of intensive induction chemotherapy.34

Heterogeneous responses to venetoclax treatment were reported in patients with AML, multiple myeloma, and non-Hodgkin lymphoma (NHL).30,35 In an attempt to improve responses, several studies investigated venetoclax in combination with other therapies. The combination of venetoclax and hypomethylating agents (decitabine or azacytidine) led to a rate of complete remission, including with incomplete count recovery, in 67% of patients in a study of patients 65 years or older (median, 74 years) with AML.36 In vitro studies have also reported responses to venetoclax in certain breast and SCLC cell lines.37,38

Recent Investigations in Breast Cancer

ABT-737 is a small molecule that was developed to match the binding pattern of BAD, which inhibited BCL-2, BCL-XL, and BCL-W, and demonstrated on-target activity and a requirement for BAK and BAX to induce apoptosis in preclinical studies.37,39,40 Navitoclax (ABT-263) is an orally bioavailable analogue. Results from preclinical studies of both ABT-737 and navitoclax demonstrated their mechanism of action, which displaced prop-apoptotic proteins containing only BH3 from BCL-2.41 In vivo study results revealed decreased platelet counts due to BCL-XL inhibition.42-45 Importantly, thrombocytopenia related to navitoclax can be controlled with appropriate dosing,46,47 leading to ongoing investigations in CLL, SCLC, and other solid tumors.48,49Based on the successful results of venetoclax treatment in hematologic malignancies, the drug is under investigation for other tumor types, including breast cancer. BCL-2 is frequently associated with estrogen receptor (ER)-positive breast cancer, of which nearly 85% of luminal tumors express elevated levels of BCL-2.50,51 BCL-2 expression has also been reported in HER2-positive tumors (approximately 50%), triple-negative breast cancers that do not have basal-like features (approximately 41%), and basal-like breast cancers (approximately 19%).52

In patient-derived xenograft models of ER-positive breast cancer, the combination of venetoclax and tamoxifen led to increased apoptosis and improved tumor response.53 Based on these findings, a phase IB dose escalation and expansion study was conducted, investigating tamoxifen 20 mg/day with 200-, 400-, 600-, or 800-mg/day venetoclax until progression. In the escalation phase, no dose-limiting toxicities or high-grade AEs were reported in 15 patients. The 800-mg/day dose of venetoclax was selected as the recommended phase II dose, as the maximum tolerated dose was not reached.

Table. Novel Agents Targeting BCL-2 Family in Clinical Trials13

In the expansion phase of 24 patients, an overall response rate of 54% and a clinical benefit rate of 75% were reported; responses included 1 complete response, 12 partial responses, and 5 patients with stable disease. Together, these results demonstrate that the combination of venetoclax and tamoxifen is safe and well tolerated, with notable clinical activity. In a study investigating dual targeting of the CDK4/6 and BCL-2 pathways using preclinical models of ER-positive and BCL-2-positive breast cancer, pro-survival BCL-2 proteins were found to be upregulated in endocrine-resistant cell lines.13 Clonogenic assays of endocrine-sensitive breast cancer cell lines treated with venetoclax, fulvestrant (Faslodex), and palbociclib (Ibrance) exhibited significantly reduced size and number of colonies compared with cell lines treated with only fulvestrant and palbociclib.

Drugs in Development

Importantly, improved tumor response and overall survival were seen in mice with ER-positive/BCL-2—positive patient-derived xenograft tumors. Together, these results support further studies evaluating combination therapy in this patient population.The approval of venetoclax is helping to pave the way for expanded exploration of the BCL-2 family. “BCL-2 family proteins are now validated as promising drug targets, with the potential to provide significant advances in the standard of care for patients suffering from oncological maladies and possibly for certain non-oncological diseases as well,” wrote John C. Reed, MD, PhD, in a recent editorial in Cell Death and Differentiation.13

Noting the focus on immunotherapy in cancer therapy, Reed said, “It will also be important to understand how BCL-2 inhibitors impact the immune system—given the role for BCL-2 in maintaining lymphocyte survival.”

There are several molecules targeting BCL-2 family proteins that are currently in various stages of development for anticancer therapy (Table).13

A phase II study is ongoing to compare the efficacy of venetoclax plus fulvestrant versus fulvestrant alone in 100 women with ER-positive/HER2-negative locally advanced or metastatic breast cancer who experienced recurrence or progression during or after CDK4/6 inhibitor treatment (NCT03584009).

A phase Ib/II study has been initiated to investigate AEs and the optimal venetoclax dose in combination with enzalutamide (Xtandi) in patients with metastatic castration- resistant prostate cancer (NCT03751436).

APG-1252 has high binding affinities to BCL-2, BCL-XL, and BCL-W. A phase I study is ongoing to determine dose-limiting toxicities, the recommended phase II dose, and the maximum tolerated dose in 50 patients with SCLC or other advanced solid tumors (NCT03387332). Other outcome measures include pharmacokinetic and pharmacodynamic evaluation.

Preliminary results have been reported from a phase I study of APG-1252 in 13 patients with advanced SCLC or other solid tumors (NCT03080311).54 The maximum tolerated dose has not been identified, and patients are currently receiving 160-mg APG-1252. Frequently reported AEs in at least 10% of patients include arthralgia, increased aspartate aminotransferase/alanine aminotransferase, fatigue, and vomiting. No AEs led to treatment discontinuation. Dose escalation and additional evaluation of APG-1252 is ongoing.

A phase I study is currently recruiting participants with relapsed or refractory solid tumors to determine the AEs and optimal dose of navitoclax in combination with sorafenib (Nexavar) tosylate (NCT02143401). A phase IB/ II study is ongoing to investigate the AEs and optimal dose of the combination of navitoclax and trametinib (Mekinist), a MEK inhibitor, in patients with advanced or metastatic solid tumors (NCT02079740).

Results from an open-label, phase I doseescalation study evaluating oral administration of S55746/BCL-201, a selective BCL-2 inhibitor, in 37 patients with relapsed or refractory NHL were recently reported.55 Subtypes of NHL included DLBCL (68%), mantle cell lymphoma (16%), FL (8%), and marginal zone lymphoma (8%). The most commonly reported grade 3 or higher AEs were lymphopenia, disease progression, and anemia. No dose-limiting toxicities or tumor lysis syndrome were reported. Among 35 evaluable patients, a complete response was reached by 1 patient with DBLCL and partial responses were achieved by 2 participants with DLBCL and 1 with FL.55 These preliminary results demonstrate an acceptable safety and tolerability profile and activity of S55746/ BCL-201 in various NHL subtypes.

Based on the crucial role of BCL-2 family proteins in apoptosis regulation, targeting these proteins using BCL-2 inhibitors offers a potentially new therapeutic option for patients with various types of hematologic malignancies and, more recently, patients with solid tumors. Recently reported and ongoing research investigating BCL-2 inhibitors as monotherapy and in combination with current systemic and targeted therapies demonstrates promising safety and efficacy results and a platform for improving treatment options and patient outcomes.

References

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