Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.

Small-molecule multi-targeted cyclin-dependent kinase (CDK) inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs.

Continuing single-agent bevacizumab as maintenance therapy after induction XELOX (or FOLFOX) plus bevacizumab in first-line treatment of metastatic colorectal cancer.

Metastatic colorectal cancer is the second leading cause of cancer death in the United States. Since 1995, treatment regimens have included capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, aflibercept, and reforafenib. These medications have doubled the median survival of patients and improved the 5-year survival from less than 1% to 20%.

Multitargeted tyrosine kinase inhibition produces discordant changes between 99mTc-MDP bone scans and other disease biomarkers: analysis of a phase II study of sunitinib for metastatic castration-resistant prostate cancer.

Unlabelled: One of the central unanswered questions in prostate cancer research is the significance of tyrosine kinase inhibitor (TKI)-induced improvements in (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans. Multitargeted tyrosine kinase inhibition has recently shown promise in the management of castration-resistant prostate cancer. In some cases, TKI inhibition has produced unprecedented improvements in bone metastases as detected by (99m)Tc-MDP bone scans.

Prospective study of changes in the metabolomic profiles of men during their first three months of androgen deprivation therapy for prostate cancer.

Purpose: Androgen deprivation therapy (ADT) for prostate cancer causes an increase in fasting insulin and adverse changes in body composition and serum lipid profile. It is unknown what other metabolic alterations are caused by ADT. To better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile at baseline and after the first 3 months of therapy.

Cyclin dependent kinases in cancer: potential for therapeutic intervention.

Cell cycle progression through each phase is regulated by heterodimers formed by cyclin-dependent kinases (CDKs) and their regulatory partner proteins, the cyclins. Together they coordinate the cellular events through cell cycle. De-regulation of cell-cycle control due to aberrant CDK activity is a common feature of most cancer types.

Posttranscriptional upregulation by microRNAs.

MicroRNAs are small non-coding RNA guide molecules that regulate gene expression via association with effector complexes and sequence-specific recognition of target sites on other RNAs; misregulated microRNA expression and functions are linked to a variety of tumors, developmental disorders, and immune disease. MicroRNAs have primarily been demonstrated to mediate posttranscriptional downregulation of expression; translational repression, and deadenylation-dependent decay of messages through partially complementary microRNA target sites in mRNA untranslated regions (UTRs). However, an emerging assortment of studies, discussed in this review, reveal that microRNAs and their associated protein complexes (microribonucleoproteins or microRNPs) can additionally function to posttranscriptionally stimulate gene expression by direct and indirect mechanisms.

Autologous stem cell transplantation with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning in patients with CNS involvement by non-Hodgkin lymphoma.

Primary central nervous system non-Hodgkin lymphoma (PCNSL) carries a poor prognosis and, although it responds to chemotherapy, fewer than 20% of patients are long-term disease-free survivors. Secondary CNS non-Hodgkin lymphoma (SCNSL) has an even worse prognosis with a median survival of only months and very few reported long-term survivors. For both of these groups of patients, there has been interest in using high-dose chemotherapy with autologous stem cell transplantation (ASCT) following conditioning with thiotepa, busulfan, and cyclophosphamide (TBC).

Corticosteroids in brain cancer patients: benefits and pitfalls.

Glucocorticoids have been used for decades in the treatment of brain tumor patients and belong to the most powerful class of agents in reducing tumor-associated edema and minimizing side effects and the risk of encephalopathy in patients undergoing radiation therapy. Unfortunately, corticosteroids are associated with numerous and well-characterized adverse effects, constituting a major challenge in patients requiring long-term application of corticosteroids. Novel antiangiogenic agents, such as bevacizumab (Avastin®), which have been increasingly used in cancer patients, are associated with significant steroid-sparing effects, allowing neuro-oncologists to reduce the overall use of corticosteroids in patients with progressive malignant brain tumors.

Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors.

Functional roles for the cancer cell-associated membrane type I matrix metalloproteinase (MT1-MMP) during early steps of the metastatic cascade in primary tumors remain unresolved. In an effort to determine its significance, we determined the in vivo effects of RNAi-mediated downregulation in mammary cancer cells on the migration, blood and lymphatic vessel invasion (LVI), and lymph node and lung metastasis. We also correlated the expression of cancer cell MT1-MMP with blood vessel invasion (BVI) in 102 breast cancer biopsies.

Chemotherapy associated central nervous system damage.

Chemotherapy is commonly associated with harmful effects to multiple organ systems, including the central nervous system (CNS). Neurotoxicity may manifest as both acute and delayed complications, which is particularly a concern for long-term survivors. Patients may experience a wide range of neurotoxic syndromes, ranging from neuro-vascular complications and focal neurological deficits to generalized neurological decline with cognitive impairment, cortical atrophy and white matter abnormalities.

Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer.

Context: Increased radiation doses improve prostate cancer control but also increase toxicity to adjacent normal tissue. Proton radiation may attenuate adverse effects.

Objective: To determine long-term, patient-reported, dose-related toxicity.

Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.

Purpose: This study aimed to test the hypothesis that elevated expression of antiapoptotic Bcl-2 family proteins predicts a poor therapeutic response of oropharyngeal squamous cell carcinoma (OPSCC) to concurrent platinum-based chemoradiation therapy.

Experimental Design: Levels of Bcl-2, Bcl-XL, and Bcl-w were determined and correlated with resistance to cisplatin in a large panel of cell lines derived from squamous cell carcinoma of the head and neck (HNSCC). Univariate and multivariate analyses were used to evaluate the relationship between Bcl-2 and Bcl-XL expression and disease-free survival following chemoradiation therapy in a uniformly treated cohort of patients with OPSCC.

A vanishing act, explained.

In a paper in this issue of Developmental Cell, Shibutani et al. (2008) uncover the mechanism that underlies tightly regulated S-phase degradation of Drosophila E2F1 during development. They show that dE2F1 is degraded by the Cul4(Cdt2) ubiquitin ligase in a manner that resembles the DNA replication-dependent turnover of Cdt1.

Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside.

Metastatic melanoma is notoriously one of the most difficult cancers to treat. Although many therapeutic regimens have been tested, very few achieve response rates greater than 25%. Given the rising incidence of melanoma and the paucity of effective treatments, there is much hope and excitement in leveraging recent genetic and molecular insights for therapeutic advantage.

The forgotten team member: meeting the needs of oncology support staff.

Introduction: The impact of working in an oncology setting has been widely researched for physicians, nurses, social workers, and chaplains. The experiences of nonlicensed support staff in an oncology setting have rarely been acknowledged or addressed. Few studies have addressed support or education initiatives for support staff caring for oncology patients.

Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms.

LKB1 is a key regulator of energy homeostasis through the activation of AMP-activated protein kinase (AMPK) and is functionally linked to vascular development, cell polarity, and tumor suppression. In humans, germ line LKB1 loss-of-function mutations cause Peutz-Jeghers syndrome (PJS), which is characterized by a predisposition to gastrointestinal neoplasms marked by a high risk of pancreatic cancer. To explore the developmental and physiological functions of Lkb1 in vivo, we examined the impact of conditional Lkb1 deletion in the pancreatic epithelium of the mouse.

E2F7 and E2F8 keep the E2F family in balance.

An article by Li and colleagues (in this issue of Developmental Cell) shows that the atypical E2Fs, E2F7 and E2F8, are critical for mouse development. One of the important functions of these family members stems from a negative feedback loop in which E2F7 and E2F8 limit the expression of E2F1 and prevent E2F1-dependent apoptosis.

Treatment 'mismatch' in early prostate cancer: do treatment choices take patient quality of life into account?

Background: Pretreatment urinary, bowel, and sexual dysfunction may increase the toxicity of prostate cancer treatments or preclude potential benefits. Using patient-reported baseline dysfunction from a prospective cohort study, we determined the proportion of patients receiving relatively contraindicated ('mismatched') treatments.

Methods: Baseline obstructive uropathy and bowel dysfunction relatively contraindicate brachytherapy (BT) and external beam radiation therapy (EBRT), respectively, because they increase patients' vulnerability to treatment-related toxicity.

Successful treatment of pure red cell aplasia with autologous stem cell transplantation.

We report a case of 64-year-old patient with pure red cell aplasia (PRCA) who was intolerant of conventional immunosuppressive therapies but achieved a complete long-term remission following autologous hematologic stem cell transplant (HSCT). The patient was initially treated with high-dose prednisone, cyclophosphamide, cyclosporine, antithymocyte globulin, and then rituximab. With the exception of rituximab, all of the above regimens achieved a transient response.

Assessing the roles of EGFR gene copy number, protein expression and mutation in predicting outcomes in non-small-cell lung cancer after treatment with EGFR inhibitors.

Evaluation of: Hirsch FR, Varella-Garcia M, Bunn PA Jr et al.: Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non-small-cell lung cancer. J.

PAK-in' up cGMP for the move.

Although guanylyl cyclases have been implicated in cell migration, how they are activated to promote cell motility is unknown. In this issue, report direct communication between guanylyl cyclases and the Rac-p21-activated kinase (PAK) signaling pathway--which is essential for cell migration--to promote cell motility, through allosteric activation of guanylyl cyclases by autophosphorylated PAK.

[Link between rheumatoid arthritis and cancer].

Because it is a systemic disorder, rheumatoid arthritis (RA) is known to predispose affected individuals to other organ manifestations as well as arthritic problems. The serious complications include pericarditis, pulmonary and cutaneous nodules, episcleritis, and rheumatoid vasculitis. Of late, a significantly increased incidence of lymphoma has also accumulated.

The retinoblastoma protein is required for Ras-induced oncogenic transformation.

Most human cancers involve either mutational activation of the Ras oncogenic pathway and/or inactivation of the retinoblastoma tumor suppressor (RB) pathway. Paradoxically, tumors that harbor Ras mutations almost invariably retain expression of a wild-type pRB protein. We explain this phenomenon by demonstrating that Ras-induced oncogenic transformation surprisingly depends on functional pRB protein.

Growth control under stress: mTOR regulation through the REDD1-TSC pathway.

Dysregulated signaling by the checkpoint kinase TOR (target of rapamycin) has been linked to numerous human cancers. The tuberous sclerosis tumor suppressors TSC1 and TSC2 form a protein complex that integrates and transmits cellular growth factor and stress signals to negatively regulate TOR activity. Several recent reports have identified the stress response gene REDD1 as an essential regulator of TOR activity through the TSC1/2 complex in both Drosophila and mammalian cells.