We have identified four cancer types for the Broadspec project that will be supported in initial case studies. This effort will involve expert support and guidance (in the development of broad-spectrum support protocols) for physicians who are treating (1) myelodysplastic syndrome patients who are at high risk of developing acute myeloid leukemia (AML); (2) advanced-stage ovarian cancer patients; (3) advanced-stage pancreatic cancer patients; and (4) glioblastoma multiforme patients.
Each of these cancer types is explained in a bit more detail below:
MDS patients at high risk of developing AML
Myelodysplastic syndromes are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. High and Very High risk MDS patients (defined by the International Prognostic Scoring System), compromise a third of MDS patients28 and have a median survival of 1.6 and 0.8 years, respectively1,2.
Currently Food and Drug administration (FDA)-approved drugs for the treatment of MDS are not curative and their effect on survival is limited. These medications include the hypomethylating agents azacitidine and decitabine and also lenalidomide (for MDS with isolated del(5q)). To date, allogeneic stem cell transplant remains the only treatment option for possible cure3, but many patients are not eligible for transplantation due to advanced age, or associated co-morbidities4.
About one-third of patients with MDS progress to MDS-related acute myeloid leukemia (secondary AML), an aggressive stem cell malignancy characterized by ≥20 % bone marrow (BM) blasts4. The remaining two-thirds normally succumb to progressive bone marrow failure which leads to bleeding (due to low platelet counts), recurrent infections (due to low white blood cells), and severe anemia (which requires regular transfusions and causes iron accumulation and toxicity)5. For MDS patients who do progress to secondary AML, the outcome is generally grave. Cytotoxic chemotherapy has been the most common form of treatment for the past 20 years so clinical outcome remains poor for the majority of patients6. Indeed, most patients are resistant to treatment and the long-term survival rate of treated patients is <10%5.
So a broad-spectrum prophylactic intervention that could prevent a transition to secondary AML in MDS patients would be a welcomed advance. Moreover, other targets of relevance in myelopoiesis have been identified which has spurred the development of agents for MDS (e.g., immunomodulatory agents, immunosuppressive therapies, survival signal inhibitors, thrombopoiesis-stimulating agents, pharmacologic differentiators, and anti-angiogenic and apoptotic agents)7,8 so there are many additional targets that could also be incorporated in a broad-spectrum protocol developed specifically for MDS patients.
Advanced-stage ovarian cancer
Advanced stage ovarian cancer is a disease with a high relapse rate. People with ovarian cancer can be largely asymptomatic in early stages, so more than 75% of patients are diagnosed in an advanced stage of disease (International Federation of Gynecology and Obstetrics stages III–IV)9. Surgery and chemotherapy (using taxanes and platinum compounds) can reduce tumor burden and extend survival times, but recurrence rates are higher than 80% in advanced stage patients9. Platinum-resistant ovarian cancer can be treated with cytotoxic chemotherapy (e.g., paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine)10, but there are no curative treatment options for refractory forms of the disease11 so the median survival time of patients with advanced stage disease is 65 months11.
A significant number of studies have provided insights into the molecular pathogenesis of this cancer, which can now be divided into four groupings: i) high-grade serous carcinomas; ii) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; iii) low grade serous carcinomas; and iv) mucinous carcinomas and malignant Brenner tumors12,13. As a result, a good number of rational targets have been identified14-18 and targeted therapies have shown promising results in ovarian cancer clinical trials, including treatments targeting the vascular endothelial growth factor pathway (e.g., bevacizumab and aflibercept), DNA repair mechanisms (e.g., iniparib and olaparib), and folate-related pathways (e.g., pemetrexed, farletuzumab, and vintafolide)10. So there is a shift in focus to treatments that are more subtype-specific and a belief that more robust combinations of selected actions on relevant targets (in concert with taxanes) may prove to be more effective19, making this a cancer that might benefit from a broad-spectrum methodology.
Advanced-stage pancreatic cancer
Pancreatic cancer is the third leading cause of cancer-associated deaths in the United States20. In the USA alone, approximately 53,670 people will be diagnosed with pancreatic cancer and nearly 43,090 will die from the disease in 201721. Surgical resection is usually the only chance of a cure for pancreatic cancer but given that the disease is often diagnosed in late stages, only 15%–20% of patients with pancreatic cancer are eligible for surgical resection22, and the cancer frequently recurs even after complete surgical resection23. Consequently, the median overall survival for pancreatic patients is just 2–8 months, with a five-year survival rate of 7.7%21.
Over the past few decades, the standard drugs for pancreatic cancer were 5-fluorouracil (5-FU) and gemcitabine24. Historically the success rate of 5-FU was <20% but gemcitabine offered marginally better results so it is now prescribed for the patients suffering from locally advanced (stage II or stage III) or metastatic (stage IV) pancreatic cancer25. Recently, first-line therapy with gemcitabine plus nab-paclitaxel or a regimen of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has increased the median overall survival to 8.5 months and 11 months, respectively, in patients with metastatic pancreatic cancer. This is compared to an overall survival of only 6 months prior to 201126 and the sequencing of the two regimens mentioned above has improved median overall survival to 18 months26.
Although there are multiple subtypes, the most common tumor type among pancreatic cancers is pancreatic ductal adenocarcinoma (PDAC) and the emerging molecular taxonomy of PDAC supported by next generation sequencing analyses is creating new opportunities to personalize therapeutic approaches27. However, the translation of treatment based on multiple unique targets is presenting considerable challenges in the clinic28. The results from genomic testing can take several weeks (causing unacceptable treatment delays), biopsies are not always possible, and patients are not always strong enough for this approach using existing therapies28.
Molecular targeted therapy has been extensively evaluated in pancreatic adenocarcinoma, but with very little improvement to survival29. Prospective randomized trials of irinotecan encapsulated in liposomal-based nanoparticles and other combination regimens have resulted in some improvement to patients’ outcome (as second-line therapy after disease progression) but durable responses are still rare30. Most recently, pegylated recombinant human hyaluronidase (PEGPH20), a novel agent that degrades hyaluronic acid (a major component of the extracellular matrix), has been used to target the tumor stroma. This approach has shown some promise in clinical trials and Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing (with outcomes eagerly anticipated)31.
At the same time, many NHPs have been tested in experiments designed to support conventional approaches to therapy in pancreatic, and several have been credited with improving the immune system, suppressing tumor progression, enhancing beneficial effects, and lessening adverse/side effects of chemotherapy and radiotherapy32. So, a more global integrative approach incorporating immunotherapy, cytotoxic chemotherapy and NHPs should have a greater potential for efficacy and also provide support for other treatment-related effects as well.
Glioblastoma multiforme (GBM) is the most malignant primary brain tumor in adults and the most common astrocytoma and classified as World Health Organization grade IV. Each year, about 5-6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which 80% are malignant gliomas, and half are GBM33. GBM is highly malignant and typically accompanied by extensive infiltration into the surrounding tissue. GBM often infiltrates the brain in ways that limit the potential effectiveness of surgical resection. Surgery is typically followed by a combination of radiotherapy with concurrent and adjuvant chemotherapy (i.e., temozolomide)34, but median survival is only about 15 months33.
Progress over the past decade has revealed many complex genetic alterations and genomic profiles (epigenetic and genetic alterations as well as gene/protein expression profiles) in primary and secondary tumors and in the tumor microenvironment. This has led to the first molecular/genetic classification of the disease and four well-defined genomic subtypes of GBM (i.e., classic, mesenchymal, proneural, and neural)35. So several targeted therapies have been evaluated in clinical trials, but to date, only a single anti-angiogenic agent (bevacizumab) has been approved for the treatment of recurrent GBM in the United States and Canada36.
Consequently, with their rapid diffusion, infiltrative growth and high level of cellular heterogeneity, GBM, is one of the most refractory and lethal human cancers37-39. A broad-spectrum methodology would allow us to leverage our knowledge of the many potential targets that appear to exist in these complex cancers and give us a much better chance of addressing this heterogeneity.
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- Yun S, Vincelette ND, Abraham I, Robertson KD, Fernandez-Zapico ME, Patnaik MM. Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: a systematic review of hypomethylating agents trials. Clin Epigenetics. 2016;8:68.
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- Leamon CP, Lovejoy CD, Nguyen B. Patient selection and targeted treatment in the management of platinum-resistant ovarian cancer. Pharmacogenomics and personalized medicine. 2013;6:113-125.
- Wefers C, Lambert LJ, Torensma R, Hato SV. Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence. Gynecologic oncology. 2015;137(2):335-342.
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- Schwab CL, English DP, Roque DM, Pasternak M, Santin AD. Past, present and future targets for immunotherapy in ovarian cancer. Immunotherapy. 2014;6(12):1279-1293.
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- Weinberg BA, Philip PA, Salem ME. Evolving standards of care for resected pancreatic cancer. Clinical advances in hematology & oncology : H&O. 2017;15(2):141-150.
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- Li L, Leung PS. Use of herbal medicines and natural products: an alternative approach to overcoming the apoptotic resistance of pancreatic cancer. The international journal of biochemistry & cell biology. 2014;53:224-236.
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