Dr. Weeks’ Comment: As money is flowing to companies investing in cancer STEM cell therapies even your oncologist is finally learning about the real target in cancer care – the cancer STEM cell. Here is a nice summary to help you understand the really dangerous ringleader in cancer – the cancer STEM cell.
“… Undoubtedly, the existence of CSCs has profound prognostic and therapeutic implications and is changing our fundamental understanding of cancer. Mounting evidence suggests CSCs are responsible for all of the important characteristics of tumors, from initiation to metastasis…”
During the past several decades, the existence of a group of cells possessing stem cell–like properties within the heterogeneous makeup of a tumor has been cemented and their potential role in all aspects of cancer development and progression has been uncovered. These so-called cancer stem cells (CSCs) comprise only a tiny portion of the tumor, yet they could prove to be the most important therapeutic targets in a broad range of tumor types.
Drugs that target CSCs directly are now emerging. Particular progress has been made in the development of small-molecule inhibitors of key signaling pathways that are responsible for the unique characteristics of stem cells, developed by biotechnology companies focused solely on CSC-targeting therapies.
The lead candidate in this area, BBI608, is undergoing phase III testing in gastric and gastroesophageal junction (GEJ) cancers.
Seed and Soil Theory
The long-accepted paradigm of cancer development has been that normal cells are transformed into malignant ones through the accumulation of genetic alterations in hallmark cellular processes. Identification of the molecular drivers underlying this transformation sparked a revolution in cancer therapy with the development of targeted drugs.
Despite significant promise, targeted therapies have not proved to be the “magic bullet” they were initially hailed to be. Therapeutic resistance and tumor recurrence remain significant unmet challenges, and metastatic disease is responsible for more than 90% of cancer-related deaths.
In an effort to tackle metastatic disease, researchers have been revisiting several historical theories and placing them into a modern context in cancer cell biology.
More than 150 years ago, the German pathologist Rudolf Virchow observed similarities between tumor tissue and embryonic tissue and suggested that tumors arise from the activation of embryo-like stem cells.
A few decades later, Stephen Paget postulated his seed and soil theory—that tumor metastases require a favorable interaction between the metastatic tumor cells (the seed) and their organ microenvironment (the soil).
These two concepts have been refined and married in a burgeoning field of cancer research, with the suggestion that Paget’s “seeds” are, in fact, Virchow’s “cancer stem cells.”
Cancer Stem Cells in Microenvironment
The complex role of cancer stem cells in the tumor microenvironment is believed to include self-renewal capabilities that help initiate and maintain the formation of the environment itself and promote cancer progression.
Schiavoni G, Gabriele L, Mattei F. The tumor microenvironment: a pitch for multiple players [published online April 17, 2013]. Front Oncol. 2013;3:90. doi: 10.3389/fonc.2013.00090. eCollection.
The first solid evidence of the existence of CSCs came from patients with leukemia in the 1990s. Since then, CSCs have been identified in most types of human cancer, including both solid tumors and hematologic malignancies, and have generated intense skepticism and unfettered enthusiasm in equal measure.
Undoubtedly, the existence of CSCs has profound prognostic and therapeutic implications and is changing our fundamental understanding of cancer. Mounting evidence suggests CSCs are responsible for all of the important characteristics of tumors, from initiation to metastasis.
Furthermore, because these cells are typically dormant, they are resistant to traditional therapies that target rapidly proliferating cancer cells. It is suggested that the CSCs that are left behind after treatment drive the eventual recurrence observed in almost all patients with cancer. From there it is only a small leap to suggest that eliminating CSCs could be the elusive “cure” for which cancer researchers are searching. However, although initial skepticism about the existence of CSCs has been overcome, many leading researchers remain cautious about overstating the potential of the therapeutic targeting of these cells. Indeed, CSC research presents technical challenges and many unanswered questions.
What are CSCs?
Even the definition of CSCs has proved challenging, but essentially they represent the tiny fraction of cells within a tumor that are capable of giving rise to new tumors. They were dubbed stem cells because of the parallels that can be drawn with normal stem cells, in their unique potential to develop (differentiate) into any other cell type within the tumor.One of the key questions surrounding CSC biology is where they come from, and several models have been proposed:
- Stochastic model—Suggests that all cells within the tumor are capable of becoming CSCs under the right circumstances
- Hierarchical model—Posits that CSC capabilities are limited to only a few distinct cells within the tumor.
- Dynamic model—Hypothesizes that CSCs may derive from fully differentiated cancer cells that revert back to a CSC state Several different subsets of CSCs have also been suggested to exist, from precancerous stem cells to primary CSCs and migratory CSCs.
Regardless of their origins, CSCs represent only a very small percentage of the tumor cell population at any one time. Defining and identifying these cells for each tumor type has presented a substantial technical hurdle. Dozens of CSC markers have been identified to assist in the challenge, including proteins such as CD133, CD44, CD24, epithelial cell adhesion molecule (EpCAM), and ATP-binding cassette subfamily B member 5 (ABCB5). CSCs are isolated from the heterogeneous tumor cell population using fluorescence-activated cell sorting (FACS) and are transplanted into mouse models to determine their tumor-forming potential.
Nonetheless, simple, rigorous, and gold-standard assays are still lacking.
Strategies to Target Stem Cells
Despite the obvious challenges, the unprecedented potential of CSCs as a therapeutic target has driven intensive research efforts in this area over the past two decades. A host of different means of targeting CSCs have been proposed, but for the most part remain in the preclinical stages.
These approaches include targeting CSC-specific cell surface markers, inducing differentiation of CSCs to block their stemness, and enhancing their sensitization to traditional therapies using a variety of techniques such as RNA interference, micro RNA, small-molecule inhibitors, biologics, and naturally occurring compounds.
Research has now expanded into identifying other proteins that are key to a cancer’s stemness—the unique properties of CSCs—the targeting of which would offer the opportunity to specifically kill CSCs or to “switch off” the stemness by driving the CSCs into a differentiated state. Two Boston-based companies, Boston Biomedical and Verastem, have emerged as key players in this arena.
As with other cancer cells, a characteristic of CSCs is their accumulation of genetic alterations that drive cellular signaling pathways to go awry. Early clinical efforts focused on targeting key signaling pathways found in stem cells, predominantly honing in on three key pathways: Hedgehog (Hh), Notch, and Wnt.These pathways also play important roles in regulating the tumor microenvironment (the “soil”), which is important in supporting the growth and development of the CSCs and has also been dubbed the CSC niche. Essentially, there are two approaches to targting CSCs: Drugs developed specifically with CSCs in mind and agents active in cell-signaling networks now regognized as pathways where CSCs play an important role. (Table).
Boston Biomedical is using proprietary platform technologies to focus on the development of CSC-targeting therapies. The company’s lead drug, BBI608, is currently the most advanced CSC-targeting drug in clinical development. It acts as an inhibitor of STAT3, a transcription factor that regulates a myriad of genes involved in cancer stemness.
Table. Cancer Stem Cell Pathway Drugs Under Development
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; CRC, colorectal cancer; GEJ, gastroesophageal junction cancer; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; MDS, myelodysplastic syndrome; NSCLC, non–small cell lung cancer; SCLC, small cell lung cancer; TNBC, triple-negative breast cancer.
A host of data were presented at recent meetings, including the results of a phase Ib/II extension study of BBI608 (480 or 500 mg twice daily) in combination with paclitaxel (80 mg/m2 IV weekly 3 of every 4 weeks) in advanced gastric/GEJ cancer. In heavily pretreated patients who had failed an average of more than two lines of prior therapy, objective responses, lesion regression, and prolonged stable disease were reported.
In a subset of patients who had received only one prior line of therapy and who had not received prior therapy with a taxane in the metastatic setting, the overall response rate (ORR) was 50% (3 of 6 patients) and the disease control rate (DCR) was 83% (4 of 6 patients). The most common adverse events (AEs) were grade 1/2 diarrhea, nausea, and abdominal pain.
BBI608 is now being evaluated in this setting in the phase III BRIGHTER trial, which seeks to randomize 700 participants to BBI608 plus paclitaxel versus paclitaxel with a placebo (NCT02178956).
BBI608 is also being evaluated in a phase III trial in combination with best supportive care in patients with advanced colorectal cancer (CRC) (NCT01830621). There also are several phase I and II trials of BBI608 as monotherapy and in combination with chemotherapy, molecularly targeted therapies, and immunotherapy in the setting of hepatocellular carcinoma, glioblastoma, pancreatic cancer, and other advanced solid tumors and hematologic malignancies. Data from two phase Ib studies of BBI608 in metastatic CRC were presented recently. In combination with FOLFIRI, with or without bevacizumab, DCR was 100%, including one patient with a partial response (PR) and eight with stable disease (SD) with tumor size reduction. The median progression- free survival (PFS) was 23.7 weeks.
In combination with panitumumab in nine patients with KRAS wild-type disease, the DCR was 44% (including 22% PRs) in patients who had not received prior EGFR therapy, compared with a DCR of 53.3% (SD only) in patients who had prior anti-EGFR therapy. In both trials, the combinations were well tolerated, with safety profiles similar to that of each individual agent.
Boston Biomedical also is developing BBI503, which it describes as an inhibitor of stemness proteins, including Nanog, a transcription factor that is critically involved in self renewal of stem cells. It is currently being evaluated in phase II clinical trials in patients with advanced hepatobiliary cancer, gastrointestinal stromal tumors, and urologic malignancies (NCT02232633, NCT02232620, and NCT02232646) and in asymptomatic patients with recurrent ovarian cancer with CA-125 elevation (NCT02432690).
The results of a phase I extension study of BBI503 as monotherapy in patients with advanced CRC were presented at the 2015 ASCO Annual Meeting. The drug was well tolerated at the recommended phase II dose of 300 mg once daily. Patients with high Nanog expression experienced a significantly higher DCR (56%) compared with those with Nanog-negative tumors (13%) The AE profile was similar to that of BBI608.
Verastem is developing inhibitors of focal adhesion kinase (FAK), an enzyme involved in cellular adhesion and motility, which has been shown to play a key role in the interaction between CSCs and their microenvironment that is thought to regulate stemness.
In September 2015, Verastem suffered disappointment when the phase II COMMAND trial of its lead compound defactinib (VS-6063) in patients with mesothelioma was stopped early when it failed to show a significant level of efficacy at interim analysis.
Other phase II trials of defactinib in mesothelioma and other trials in different cancer types are ongoing,including in non–small cell lung cancer and advanced refractory solid tumors or lymphomas (NCT01951690 and NCT02465060). Verastem also has a second FAK inhibitor, VS-4718, currently undergoing phase I trials in nonhematologic malignancies.
Key Signaling Networks
The first generation of agents has proved mostly disappointing, with the exception of the Hh inhibitors vismodegib (Erivedge) and sonidegib (Odomzo). However, both drugs are approved for the treatment of basal cell carcinoma, a malignancy that is highly dependent upon activated Hh signaling and it remains unclear if targeting CSCs forms a significant part of the mechanism of action of these drugs in this setting.
Notch and Wnt
The clinical development of Notch- and Wnt-targeting agents is dominated by California-based OncoMed Pharmaceuticals.
Targeting of the Notch pathway originally focused on the use of gamma-secretase inhibitors, which block cleavage of the receptor at the cell surface, but these agents were largely discontinued due to minimal clinical activity.
Notch agents that are currently under evaluation are mostly monoclonal antibodies (mAbs) targeting the receptor or its ligands and encouraging antitumor activity has been observed in early clinical trials. These include tarextumab (OMP-59R5) and demcizumab (OMP-21M18), which have both demonstrated promising activity in advanced pancreatic cancer.
In a phase Ib trial, the combination of demcizumab plus gemcitabine and nab-paclitaxel demonstrated an ORR of 50% among 28 evaluable patients who received all three drugs, as well as a median PFS of 9 months, and a median overall survival of 10.1 months. It was generally well tolerated; fatigue, nausea, and vomiting were the most common toxicities.
The phase II YOSEMITE study of demcizumab plus nab-paclitaxel and gemcitabine in patients with first-line metastatic pancreatic ductal adenocarcinoma is ongoing; the study uses a truncated course of demcizumab in an effort to prevent onset of late reversible cardiopulmonary toxicity (NCT02289898).
Meanwhile, the phase I/II ALPINE trial evaluating tarextumab as part of a similar regimen has completed enrollment of 177 patients with previously untreated stage IV pancreatic cancer (NCT01647828).
MedImmune’s offering, MEDI0639, an mAb targeting the Notch ligand DLL4, is being evaluated in phase I clinical trials in advanced solid tumors. Preliminary data from the first 20 patients enrolled were reported at the 2015 ASCO Annual Meeting.
– The drug was found to have a manageable safety profile and evidence of antitumor activity. Phase I clinical trials of OncoMed’s lead Wnt inhibitors, vantictumab (OMP-18R5) and ipafricept (OMP-54F28), are currently ongoing after a brief partial clinical hold was placed on these agents in mid-2014. The hold was subsequently released following submission of a safety and efficacy data package and revised study protocols.
Several other drugs that target stemness are in the early stages of clinical development. Stemline Therapeutics is evaluating SL-401, an inhibitor of the interleukin-3 receptor that is present on the surface of acute myeloid leukemia stem cells, in phase I/II trials in patients with AML and advanced, high-risk myeloproliferative neoplasms (NCT02270463, NCT02113982, NCT02268253).
Reparixin is an inhibitor of the chemokine receptors CXCR1/2; similarly to FAK, chemokines are important in regulating the interaction between CSCs and the CSC niche. This agent has shown significant efficacy in breast cancer and is currently being evaluated in the phase II FRIDA trial in combination with paclitaxel in patients with metastatic triple negative breast cancer (NCT02370238).
The results from a phase Ib study in this setting were presented at the 2014 San Antonio Breast Cancer Symposium. The combination was well tolerated at all dose levels examined and efficacy was observed in both hormone receptor–positive disease and triple-negative breast cancer.
Additionally, Verastem is investigating VS-5584 as an inhibitor of phosphatidylinositol-3-kinase/ mammalian target of rapamycin (PI3K/mTOR), another signaling pathway that has been shown to be important in maintaining stemness. VS-5584 was granted orphan drug designation in mesothelioma in February 2015.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in the New Haven, Connecticut.
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– See more at: http://www.onclive.com/publications/oncology-live/2015/november-2015/cancer-stem-cells-coming-into-sharper-focus/4#sthash.YSWYJ2Vt.dpuf