Mechanism of Action: Key Advances in Hematology Oncology

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BCL-2 Inhibition: Hastening Cancer Cell Death

Lisa Raedler, PhD, RPh

All treatments for cancer either remove or kill cancer cells. Whether it is surgery, radiation, chemotherapy, or biologic therapy, the goal is to eradicate cancer cells without destroying the patient’s healthy cells. Consider the example of microtubule inhibitors (MTIs)—paclitaxel, eribulin, ixabepilone, and others. All agents in this class affect cancer cell growth by interrupting cell division. While these MTIs have clinical activity in specific subgroups of patients with breast cancer and other solid tumors, they also damage patients’ healthy cells (eg, rapidly dividing epithelial cells found in hair follicles and lining the gastrointestinal tract). BCL-2 inhibitors do not interrupt cell division; they trigger cancer cell death by targeting the cell suicide “machinery.” What do BCL-2 genes and BCL-2 proteins do in normal cells? Multicellular organisms are comprised of many types of cells that grow, develop, function, and die over a specific time frame. Programmed cell death, or apoptosis, is crucial for embryonic development, cell and tissue homeostasis, and the removal of superfluous, infected, and damaged cells. There are 2 principal pathways to apoptosis—the stress or intrinsic pathway, which involves the mitochondria of the cell, and the death receptor or extrinsic pathway.1,2 Apoptosis begins when either normal genetic signaling or a stressor (eg, toxins, heat, irradiation) triggers a cascade of biochemical events that include activation of the caspase family of enzymes. The caspases are involved in the intiation, mediation, and execution of apoptosis. Apoptosis causes changes in the cell (eg, plasma membrane blebbing, shrinkage of the cell, DNA fragmentation) that ultimately result in the breakup of the cell contents into vesicles that are consumed by other cells. Among the regulatory proteins active during the stress pathway to apoptosis are those of the BCL-2 family.1 B-cell/CLL lymphoma 2 (BCL-2) genes produce multiple BCL-2 proteins that are involved in the regulation of apoptosis in the cell. Selected BCL-2 proteins (eg, BCL-2, BCL-XL, BCL-w) are known as “antiapoptotic” or “prosurvival” because they inhibit apoptosis and extend the cell’s life. Other BCL-2 proteins (eg, Bax, Bak, Bim) facilitate cell death, and are called “proapoptotic.” In normal cells, the determination of continued life or death is balanced, in part, by this family of BCL-2 proteins.1 What do BCL-2 genes and BCL-2 proteins do in cancer cells? In various conditions, including autoimmune diseases, neurodegenerative disorders, and cancer, there is a disturbance in the balance of cell growth and cell death. In cancer, apoptosis is insufficient, resulting in uncontrolled cell proliferation. Cancer cells are able to live beyond their typical life span and convey their faulty cell-death machinery to progeny when they replicate.2 A new era in cancer cell death research was launched more than 25 years ago with the discovery of the BCL-2 genes. Scientists studying BCL-2 learned that defective apoptosis regulation in cells contributes to cancer, marking a major step forward in our understanding of tumor growth.3 Specifically, researchers learned that cancer cells may overexpress antiapoptotic proteins and/or suppress apoptotic proteins.4 As shown in the Figure, interactions between 3 factions of the BCL-2 protein family determine whether or not a cell will undergo apoptosis in response to stress: (1) BH3-only proteins, (2) their prosurvival relatives, and (3) their proapoptotic relatives, which commit the cell to apoptosis by rendering the outer membranes of the cell’s mitochondria permeable. BH3-only proteins engage the prosurvival proteins guarding Bax/Bak, allowing activation of Bax/Bak and starting the death process for the cell. In cancer cells, the overexpression of a prosurvival protein or suppression of a proapoptotic protein can tip the balance away from apoptosis.5 figure Why target BCL-2 genes and BCL-2 proteins in cancer? The complex process of apoptosis in cancer cells is now known to be affected by many signaling pathways: the death receptor, the Smac (second mitochondria-derived activator of apoptosis), the Myc, the MAPK/JNK (mitogen-activated protein kinase superfamily member c-Jun N-terminal protein kinase), and the NF-κB (nuclear factor kappa B) pathways are just a few.1,6 Several approaches to facilitating apoptosis in cancer cells are currently under study, including increasing the number of death receptor ligands (eg, tumor necrosis factor–related apoptosis-inducing ligand [TRAIL]), supplementing Smac, and antagonizing the antiapoptotic BCL-2 pathway.5 Targeting BCL-2 is an attractive and rational strategy because BCL-2 gene mutations and BCL-2 protein overexpression are clearly associated with various cancers. BCL-2 gene mutations occur in approximately 90% of follicular lymphomas and approximately 28% of diffuse large cell lymphomas.7-9 Additionally, BCL-2 proteins are moderately to highly overexpressed in lung, prostate, breast, ovarian, and renal cancer, as well as glioma, leukemia/lymphoma, and melanoma. Damaged BCL-2 genes can result in unchecked cancer cell growth, unfavorable prognosis, and cancer treatment resistance for these patients.9 What is known about the clinical activity of BCL-2 inhibitors? Several experimental therapies that target BCL-2 proteins are now or have recently been in preclinical and clinical testing (Table), raising hopes that a new class of anticancer drugs may be near.3,5 The first agent to target BCL-2 that entered human clinical trials was the antisense oligonucleotide oblimersen sodium (Genasense, Genta). Preclinical data led to the hypothesis that concomitant use of oblimersen and chemotherapy can sensitize cancers to chemotherapy by downregulating BCL-2, and a number of combination studies were undertaken.10 table In a phase 3 trial in patients with relapsed and refractory chronic lymphocytic leukemia (CLL), oblimersen demonstrated a significant improvement in complete and nodular partial response when combined with chemotherapy.10 Results in other combination studies with oblimersen suggested clinical value in other tumor types. Several phase 3 studies of oblimersen, however, failed to demonstrate an overall survival benefit.10 Oblimersen was not approved by the US Food and Drug Administration. More recent advances have focused on small molecule BCL-2 protein inhibitors. These BH3 mimetic agents bind the hydrophobic groove of antiapoptotic BCL-2 proteins in place of BH3-only proteins.10 There are 2 small molecule BCL-2 inhibitors currently in development: GDC-0199 (also known as ABT-199) and sabutoclax (ONT-701). The development of 3 other small molecule BCL-2 inhibitors, ABT-737, navitoclax (ABT-263), and obatoclax (GX15-070), has been discontinued. Both ABT-737 and navitoclax, an oral derivative of ABT-737, avidly bind to multiple BCL-2 proteins, including BCL-2, BCL-XL, and BCL-w. Both showed activity in preclinical studies, and navitoclax showed activity in earlyphase clinical trials. However, their interaction with BCL-XL provoked significant thrombocytopenia, a dose-limiting toxicity,11 and both products have been discontinued in favor of GDC-0199 (ABT-199). GDC-0199 (ABT-199) GDC-0199, also known as ABT-199, is a selective inhibitor of BCL-2 proteins and a BH3 mimetic. Jointly developed by AbbVie and Genentech, the agent is currently in phase 1/1b clinical trials for the treatment of patients with relapsed or refractory CLL, non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).11 Unlike its predecessors, ABT-737 and ABT-263, the re-engineered GDC-0199 (ABT-199) appears to have potent antitumor activity while sparing platelets.17,18 In preclinical testing, GDC-0199 (ABT-199) was evaluated against aggressive progenitor cell lymphomas derived from bitransgenic Myc/Bcl-2 mice. In this study, single-agent GDC-0199 (ABT-199) was as effective as ABT-737 in prolonging the survival of tumor-bearing mice without causing thrombocytopenia.11 In the clinic, single doses of GDC-0199 (ABT-199) in 3 patients with refractory CLL resulted in tumor lysis within 24 hours, indicating that selective inhibition of BCL-2 is a promising treatment for BCL-2–dependent hematologic cancers.19 In June 2013, results of a phase 1, open-label, multicenter, international trial of GDC-0199 (ABT-199) in patients with relapsed or refractory CLL and NHL were presented at the annual meeting of the American Society of Clinical Oncology.12,13 Among the 56 patients enrolled in the CLL arm of the trial, the most common non-hematologic adverse events (AEs) were nausea, diarrhea, fatigue, upper respiratory tract infection, and cough. Tumor lysis syndrome (TLS) occurred in all 3 patients with CLL in the first dose group in the GDC-0199 (ABT-199) trial. Upon dose reduction and schedule modification, 3 of 53 patients experienced TLS. One fatality occurred in a patient with CLL with laboratory evidence of TLS.12 Single-agent activity was observed with GDC-0199 (ABT-199) in the CLL trial. Preliminary efficacy results showed that 46 of 55 patients (84%) achieved a response to GDC-0199 (ABT-199): 10 patients achieved complete response (CR) or CR with incomplete bone marrow recovery; 36 patients achieved partial response (PR). The study also demonstrated GDC-0199 (ABT-199) activity in high-risk patients with CLL. PR was achieved by 13 of 16 patients with 17p deletion and 14 of 18 patients with fludarabinerefractory CLL.12 In the second arm of the GDC-0199 (ABT-199) trial, 32 relapsed or refractory patients with NHL were enrolled. The most common AEs in this trial were nausea, diarrhea, dyspepsia, vomiting, fatigue, fever, and cough. Grade 3 or 4 AEs occurring in more than 1 patient included anemia, neutropenia, febrile neutropenia, and thrombocytopenia. Grade 3 or 4 thrombocytopenia was not dose dependent. Grade 3 TLS was seen after the initial dose in 1 patient with bulky mantle cell lymphoma.13 Preliminary efficacy results in the phase 1 trial of GDC-0199 (ABT-199) in NHL showed 17 of 32 patients (53%) achieved a response, with 1 patient experiencing CR and 16 patients experiencing PR.13 Both arms of this study continue to accrue.20 According to ClinicalTrials.gov, several phase 1/1b clinical trials of GDC-0199 (ABT-199) are currently recruiting hematologic malignancies20:
  • Relapsed or refractory CLL
    • Single agent GDC-0199 (ABT-199) (all patients)
    • Single agent GDC-0199 (ABT-199) (patients with 17p deletion)
    • GDC-0199 (ABT-199) in combination with rituximab
  • Relapsed or refractory NHL
    • Single agent GDC-0199 (ABT-199)
    • GDC-0199 (ABT-199) in combination with bendamustine and rituximab.
  • Relapsed or refractory MM
    • Single agent GDC-0199 (ABT-199)
    • GDC-0199 (ABT-199) in combination with bortezomib and dexamethasone.
In addition to clinical research with GDC-0199 (ABT-199), translational work is under way to understand the mechanisms of treatment resistance in patients with relapsed CLL, including the interaction of BCL-2–mediated apoptosis and proapoptotic and prosurvival signals that are initiated in the tumor cell microenvironment. Using BH3 profiling, researchers have learned that CLL cells cocultured with stroma are less susceptible to apoptosis in response to BCL-2 inhibition. This suggests that BH3 profiling of patients with CLL may help oncologists predict response to GDC-0199 (ABT-199), as well as help identify resistance mechanisms to other new agents being studied in patients with CLL.21 Experts believe that these assays will be critical in determining how best to incorporate GDC-0199 (ABT-199) into the armamentarium of cancer therapies for patients with CLL and other hematologic malignancies.17 ONT-701 (Sabutoclax) As of June 2013, ONT-701 (sabutoclax) is the only pan–BCL-2 inhibitor in development. It is derived from apogossypol, a synthesized version of gossypol (a cottonseed extract), and is currently in preclinical testing.22-25 Published preclinical data suggest that sabutoclax, which suppresses all BCL-2 antiapoptotic proteins, may obviate resistance to standard chronic myelogenous leukemia drugs, including tyrosine kinase inhibitors.26 Further plans for the drug’s clinical development have not been made public by its Seattle based developer, Oncothyreon. What are the next steps in BCL-2 science and drug development? With the cloning of BCL-2 more than 25 years ago, the BCL-2 family of proteins became an exciting target for cancer researchers. Since their initial discovery, specific ways in which BCL-2 genes and proteins control if and when the cell undergoes apoptosis have been explored and clarified. Despite initial setbacks, several agents that inhibit BCL-2 and related antiapoptotic proteins show considerable clinical promise in various hematologic malignancies and solid tumors. Expanding knowledge of the BCL-2 family has also enhanced understanding of how conventional chemotherapy targets cancer cells, and why some cancers are more sensitive than others to chemotherapy.27 For BCL-2 inhibitors that are in or approaching clinical development, challenges include toxicities such as thrombocytopenia and TLS as well as the development of resistance. To mitigate toxicity risk, alterations in dosing and scheduling, and use of premedication may be necessary. Translational research is under way to develop and evaluate assays that predict the efficacy of BCL-2 inhibitors and to clarify resistance mechanisms to BCL-2 inhibitors. Continued research into the BCL-2 family promises improved predictive biomarkers for oncologists and superior apoptosis-directed treatments for patients with advanced cancer.

References

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