Ralph J. Hauke

Stem Cells: A Revolution in Therapeutics—Recent Advances in Stem Cell Biology and Their Therapeutic Applications in Regenerative Medicine and Cancer Therapies

Basic and clinical research accomplished during the last few years on embryonic, fetal, amniotic, umbilical cord blood, and adult stem cells has constituted a revolution in regenerative medicine and cancer therapies by providing the possibility of generating multiple therapeutically useful cell types. These new cells could be used for treating numerous genetic and degenerative disorders. Among them, age‐related functional defects, hematopoietic and immune system disorders, heart failures, chronic liver injuries, diabetes, Parkinsons and Alzheimers diseases, arthritis, and muscular, skin, lung, eye, and digestive disorders as well as aggressive and recurrent cancers could be successfully treated by stem cell‐based therapies. This review focuses on the recent advancements in adult stem cell biology in normal and pathological conditions. We describe how these results have improved our understanding on critical and unique functions of these rare sub‐populations of multipotent and undifferentiated cells with an unlimited self‐renewal capacity and high plasticity. Finally, we discuss some major advances to translate the experimental models on ex vivo and in vivo expanded and/or differentiated stem cells into clinical applications for the development of novel cellular therapies aimed at repairing genetically altered or damaged tissues/organs in humans. A particular emphasis is made on the therapeutic potential of different tissue‐resident adult stem cell types and their in vivo modulation for treating and curing specific pathological disorders.

Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers

•  Introduction •  Functions of cancer progenitor cells in the cancer initiation and progression ‐  New model of carcinogenesis based on the cancer progenitor cells ‐  Isolation and ex vitro and in vivo characterization of functional properties of cancer progenitor cells ‐  Functions of cancer progenitor cells in the cancer development ‐  Influence of local tumour microenvironment on the behavior of cancer progenitor cells •  Cancer types originating from cancer progenitor cells ‐  New concepts of the heterogeneity of cancers derived from distinct cancer progenitor cells ‐  Implication of cancer progenitor cells in bone marrow‐derived cancers ‐  Leukaemias ‐  Sarcomas ‐  Implication of cancer progenitor cells in pediatric and adult brain tumors ‐  Implication of cancer progenitor cells in other cancer types •  Novel cancer therapies by molecular targeting of cancer progenitor cells and their microenvironment ‐  New concepts on the functions of cancer progenitor cells in the resistance to current cancer therapies ‐  New combination therapies against the aggressive and recurrent cancers ‐  Targeting cancer progenitor cells ‐  Targeting the local microenvironment of cancer progenitor cells •  Conclusions •  Future directions and perspectives

Recent Advances on the Molecular Mechanisms Involved in the Drug Resistance of Cancer Cells and Novel Targeting Therapies

This review summarizes the recent knowledge obtained on the molecular mechanisms involved in the intrinsic and acquired resistance of cancer cells to current cancer therapies. We describe the cascades that are often altered in cancer cells during cancer progression that may contribute in a crucial manner to drug resistance and disease relapse. The emphasis is on the implication of ATP‐binding cassette (ABC) multidrug efflux transporters in drug disposition and antiapoptotic factors, including epidermal growth factor receptor cascades and deregulated enzymes in ceramide metabolic pathways. The altered expression and activity of these signaling elements may have a critical role in the resistance of cancer cells to cytotoxic effects induced by diverse chemotherapeutic drugs and cancer recurrence. Of therapeutic interest, new strategies for reversing the multidrug resistance and developing more effective clinical treatments against the highly aggressive, metastatic, and recurrent cancers, based on the molecular targeting of the cancer progenitor cells and their further differentiated progeny, are also described.

Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance)

PURPOSE Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer. PATIENTS AND METHODS Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply. RESULTS Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups. CONCLUSION In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cells.

Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone‐refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine‐ and docetaxel‐induced cell growth suppression of androgen‐independent prostate cancer cells. In androgen‐independent C‐81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl‐2 by increasing phosphorylated Bcl‐2 by more than 6‐fold and Bax expression by 3‐fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl‐2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl‐2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel‐induced growth suppression in PC‐3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone‐refractory prostate cancer.

Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement

PURPOSE To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the European Association of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting the use of chemoradiotherapy for select patients with MIBC and recommending a preference for clinical trials in the treatment of metastatic disease in the second-line setting. RECOMMENDATIONS Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is recommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin.Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki.

Developing a Service Model That Integrates Palliative Care Throughout Cancer Care: The Time Is Now

Palliative care is a fundamental component of cancer care. As part of the 2011 to 2012 Leadership Development Program (LDP) of the American Society of Clinical Oncology (ASCO), a group of participants was charged with advising ASCO on how to develop a service model integrating palliative care throughout the continuum of cancer care. This article presents the findings of the LDP group. The group focused on the process of palliative care delivery in the oncology setting. We identified key elements for models of palliative care in various settings to be potentially equitable, sustainable, feasible, and acceptable, and here we describe a dynamic model for the integrated, simultaneous implementation of palliative care into oncology practice. We also discuss critical considerations to better integrate palliative care into oncology, including raising consciousness and educating both providers and the public about the importance of palliative care; coordinating palliative care efforts through strengthening affiliations and/or developing new partnerships; prospectively evaluating the impact of palliative care on patient and provider satisfaction, quality improvement, and cost savings; and ensuring sustainability through adequate reimbursement and incentives, including linkage of performance data to quality indicators, and coordination with training efforts and maintenance of certification requirements for providers. In light of these findings, we believe the confluence of increasing importance of incorporation of palliative care education in oncology education, emphasis on value-based care, growing use of technology, and potential cost savings makes developing and incorporating palliative care into current service models a meaningful goal.

Epstein–Barr virus-associated lymphoproliferative disorder after autologous bone marrow transplantation: report of two cases

Epstein–Barr virus-associated lymphoproliferative disorders have been frequently reported as a complication of solid organ and allogeneic bone marrow transplantation. Their occurrence is rare after autologous bone marrow transplantation (BMT) with only five published reports in the literature. We report two cases of post-transplant lymphoproliferative disorder occurring after autologous BMT for Hodgkin’s disease and non-Hodgkin’s lymphoma. Post-transplant lymphoproliferative disorders can occur after autologous BMT and should be included in the differential diagnosis of patients with persistent fever, adenopathy or pulmonary infiltrates.

Functions of Normal and Malignant Prostatic Stem/Progenitor Cells in Tissue Regeneration and Cancer Progression and Novel Targeting Therapies

This review summarizes the recent advancements that have improved our understanding of the functions of prostatic stem/progenitor cells in maintaining homeostasis of the prostate gland. We also describe the oncogenic events that may contribute to their malignant transformation into prostatic cancer stem/progenitor cells during cancer initiation and progression to metastatic disease stages. The molecular mechanisms that may contribute to the intrinsic or the acquisition of a resistant phenotype by the prostatic cancer stem/progenitor cells and their differentiated progenies with a luminal phenotype to the current therapies and disease relapse are also reviewed. The emphasis is on the critical functions of distinct tumorigenic signaling cascades induced through the epidermal growth factor system, hedgehog, Wnt/beta-catenin, and/or stromal cell-derived factor-1/CXC chemokine receptor-4 pathways as well as the deregulated apoptotic signaling elements and ATP-binding cassette multidrug transporter. Of particular therapeutic interest, we also discuss the potential beneficial effects associated with the targeting of these signaling elements to overcome the resistance to current treatments and prostate cancer recurrence. The combined targeted strategies toward distinct oncogenic signaling cascades in prostatic cancer stem/progenitor cells and their progenies as well as their local microenvironment, which could improve the efficacy of current clinical chemotherapeutic treatments against incurable, androgen-independent, and metastatic prostate cancers, are also described.

Prostate cancer survivorship care guideline: American society of clinical oncology clinical practice guideline endorsement

PURPOSE The guideline aims to optimize health and quality of life for the post-treatment prostate cancer survivor by comprehensively addressing components of follow-up care, including health promotion, prostate cancer surveillance, screening for new cancers, long-term and late functional effects of the disease and its treatment, psychosocial issues, and coordination of care between the survivors primary care physician and prostate cancer specialist. METHODS The American Cancer Society (ACS) Prostate Cancer Survivorship Care Guidelines were reviewed for developmental rigor by methodologists. The American Society of Clinical Oncology (ASCO) Endorsement Panel reviewed the content and recommendations, offering modifications and/or qualifying statements when deemed necessary. RESULTS The ASCO Endorsement Panel determined that the recommendations from the 2014 ACS Prostate Cancer Survivorship Care Guidelines are clear, thorough, and relevant, despite the limited availability of high-quality evidence to support many of the recommendations. ASCO endorses the ACS Prostate Cancer Survivorship Care Guidelines, with a number of qualifying statements and modifications. RECOMMENDATIONS Assess information needs related to prostate cancer, prostate cancer treatment, adverse effects, and other health concerns and provide or refer survivors to appropriate resources. Measure prostate-specific antigen (PSA) level every 6 to 12 months for the first 5 years and then annually, considering more frequent evaluation in men at high risk for recurrence and in candidates for salvage therapy. Refer survivors with elevated or increasing PSA levels back to their primary treating physician for evaluation and management. Adhere to ACS guidelines for the early detection of cancer. Assess and manage physical and psychosocial effects of prostate cancer and its treatment. Annually assess for the presence of long-term or late effects of prostate cancer and its treatment.