We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational ...treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.
What's new?
Brain metastases are difficult to treat and generally lethal. Here, the authors sought clues to possible treatment targets by comparing the molecular characteristics of lung, breast, and skin cancers with those of brain metastases. They analyzed DNA sequence, protein expression, and gene amplification on over 17,000 samples, the largest metastases cohort ever studied. They found that the enzyme TOP2A, involved in DNA transcription, was enriched in the metastatic cells relative to the primary tumor cells. Other enzymes, involved in DNA synthesis, repair, and replication were also overexpressed in metastases, and could potentially be useful therapeutic targets.
In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug ...adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells' growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass-by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs-celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan-to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of-not a replacement for-previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.
To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs) ...(monocyte, macrophage, microglia, dendritic cells) that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%-30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic - minocycline, an antihypertensive drug - telmisartan, and a bisphosphonate - zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid - the MTZ Regimen - have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low drug cost. Four core observations support this approach: 1) malignant glioblastoma cells require a reciprocal trophic relationship with nonmalignant macrophages or microglia to thrive; 2) glioblastoma cells secrete MCP-1 to start the cycle, attracting MLCs, which subsequently also secrete MCP-1 perpetuating the recruitment cycle; 3) increasing cytokine levels in the tumor environment generate further immunosuppression and tumor growth; and 4) MTZ regimen may impede MCP-1-driven processes, thereby interfering with glioblastoma growth.
Purpose
Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB ...transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers.
Methods
We retrospectively reviewed records from virtual MTBs held between 04/2020–03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions.
Results
During 25 meetings, 32 presenters discussed 44 cases. Approximately half (
n
= 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (
n
= 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (
n
= 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (
n
= 13), enrollment in the observational NCI Natural History Study to 21% (
n
= 9), neuropathology review and molecular testing at the NIH to 17% (
n
= 7), and all received management suggestions.
Conclusion
Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.
Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of many malignancies. Ifosfamide-induced encephalopathy is one potential side effect that represents a major drawback to ...ifosfamide therapy and often necessitates discontinuation of chemotherapy. Previous reports demonstrate moderate effectiveness of prophylactic methylene blue at thwarting ifosfamide-induced encephalopathy. This is a report of a 64-year-old female with relapsed double-hit diffuse large B-cell lymphoma who developed severe altered mental status and neurological symptoms after receiving a second dose of ifosfamide as part of her salvage standard dose R-IE (rituximab, ifosfamide, etoposide), in preparation for chimeric antigen receptor T-cell therapy. Ifosfamide was stopped and extensive metabolic and infectious workups, in addition to brain images, were all unremarkable. Her symptoms were attributed to ifosfamide. Prior to initiating cycle 2 of R-IE, she was started on prophylactic oral thiamine 100 mg, once a day, one week prior to her admission, methylene blue 50 mg intravenous every 6 h (for a total of four doses) and intravenous hydration with normal saline starting on day one of admission. Ifosfamide was administered in the standard dose 2000 mg/m2, days 1–3 as continuous intravenous infusion over 24 h. She tolerated the first two days of ifosfamide well and only developed mild encephalopathy during her last dose of ifosfamide. Her symptoms resolved completely without any intervention the following day and she completed all scheduled doses. She eventually received chimeric antigen receptor T-cell therapy. Our report demonstrates the use of hydration, methylene blue, and thiamine as a successful secondary prevention regimen for ifosfamide-induced encephalopathy.
Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy.
The primary objective of this ...factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide.
The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia.
The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma.
NCT00112502.
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as ...the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity.
The War on Cancer began with President Nixon’s National Cancer Act of 1971. Treatment-related ‘collateral damage’ to healthy cells and tissues that reduces quality of life is an unfortunate but ...inevitable consequence of the overriding imperative to “win the war.” In the face of a quality of life decrement, patients are encouraged with militaristic turns-of-phrases to “soldier on,” “fight it,” and “never say die.” Rather than this dysfunctional imagery, which relegates patients to the status of mere cogs in the ever-grinding wheel of the clinical war machine and encourages the practice of disease-centered medicine, we propose an alternate analogy/organizing principle borrowed from the realm of education: No patient left behind.
Background: Histologic variants of conventional glioblastoma are rare clinical entities. In recent years, an aggressive variant termed malignant glioma with primitive neuroectodermal tumor components ...(MG-PNET) has been described in adults. In addition to the rarity of supratentorial primitive neuroectdoermal tumors (sPNET) in adults, MG-PNET can present with unique radiographic features.
Case Description: We report the case of a 42-year-old male who presented with headaches and vision changes. Magnetic resonance imaging (MRI) of the brain revealed a large right frontal lesion. He underwent craniotomy with pathology demonstrating glioblastoma WHO grade IV, with primitive neuroectodermal tumor-like components (MG-PNET). Seven weeks later the patient represented with worsening headaches and left-hand weakness. MRI brain revealed a diffusion restricting subdural collection overlying the prior craniotomy site. Biopsy revealed PNET-like recurrence of the previously treated MG-PNET.
Conclusion: In addition to histologic deviation, MG-PNET can present with variable radiographic findings on MRI and a clinical course distinctive from traditional glioblastoma. The hypercellular nature of this lesion can present as a diffusion-restricting lesion.
Abstract
Some non-oncology drugs can be repurposed as adjuvants to traditional cytotoxic chemotherapies. Cancer after all uses dysregulated and pathologically activated, but otherwise normal, ...physiological growth factors, anti-apoptosis pathways and migration mechanisms. We manipulate these pathways every day in non-cancer medicine so it is straightforward to use these non-cancer related medicines to address dysregulated growth systems in cancer. We report here a 28 y/o man diagnosed in May 2011 with Grade II/III Astrocytoma, 1p/19q intact, IDH1 R132H wild type. Subtotal resection left mass-like FLAIR involving right internal capsule along with patchy enhancement. After 1 year of 5-day temozolomide, 20 mg bid, ending in Sept 2012, he was followed with serial MRI scans. After progression of enhancing tumor in May 2015, repeat biopsy demonstrated anaplastic (gemistocytic) astrocytoma. Radiation/temozolomide/naltrexone was followed by adjuvant therapy temozolomide 20 mg BID, celecoxib 200 mg daily, naltrexone 25 mg daily, and levetiracetam 1500 mg BID for seizure control. In June 2017 new enhancement appeared deep to the surgical cavity. On patient’s initiative, addition of valproic acid 500 mg BID to current therapy. He has tolerated this ongoing treatment with no toxicities and remained clinically asymptomatic, continuing to work full time. Over the interval (mid-2017 to summer 2018), the enhancing components of the tumor, which had persisted for years, have completely resolved. CONCLUSION: Repurposed drug cocktails, which can simultaneously and specifically target multiple tumor pathways remain a largely untested treatment for patients who face limited proven options. We report a patient who continues to do well in the face of an inoperable, poor molecular profile recurrent tumor with a inexpensive drug regimen that has yielded no toxicity. Repurposing non-oncology drugs to augment traditional cytotoxic chemotherapy hold great promise.
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