Multiple Myeloma Treatment Options

Treatment options for relapsing/progressing multiple myeloma; abstract:

Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.Leukemia advance online publication, 19 December 2017; doi:10.1038/leu.2017.329.

Immune Checkpoint Inhibitor Therapy Biomarkers

Immune checkpoints dampen the immune system’s ability to detect and fight cancer; thus, inhibits of such checkpoints, usually antibodies to checkpoint factors, have utility for immunotherapy against cancer.  Clinical success has been varied, and it would be helpful to identify biomarkers to ascertain what patients would most benefit by this therapeutic approach.  This study identifies some prospective markers that require more conformation.  Abstract:

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel. The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

Ginseng Product

Another natural product against cancer that affects Wnt signaling; abstract:

BACKGROUND:

AD-2 (20(R)-dammarane-3b, 12b, 20, 25-tetrol; 25-OH-PPD) is a ginsenoside and isolated from Panax ginseng, showing anticancer activity against extensive human cancer cell lines. In this study, effects and mechanisms of 1C ((20R)-3b-O-(L-alanyl)-dammarane-12b, 20, 25-triol), a modified version of AD-2, were evaluated for its development as a novel anticancer drug.

METHODS:

MTT assay was performed to evaluate cell cytotoxic activity. Cell cycle and levels of reactive oxygen species (ROS) were determined using flow cytometry analysis. Western blotting was employed to analyze signaling pathways.

RESULTS:

1C concentration-dependently reduces prostate cancer cell viability without affecting normal human gastric epithelial cell line-1 viability. In LNCaP prostate cancer cells, 1C triggered apoptosis via Bcl-2 family-mediated mitochondria pathway, downregulated expression of mouse double minute 2, upregulated expression of p53 and stimulated ROS production. ROS scavenger, N-acetylcysteine, can attenuate 1C-induced apoptosis. 1C also inhibited the proliferation of LNCaP cells through inhibition on Wnt/β-catenin signaling pathway.

CONCLUSION:

1C shows obvious anticancer activity based on inducing cell apoptosis by Bcl-2 family-mediated mitochondria pathway and ROS production, inhibiting Wnt/β-catenin signaling pathway. These findings demonstrate that 1C may provide leads as a potential agent for cancer therapy.

Ovarian Cancer Vaccine

Personalized cancer vaccine for ovarian cancer; abstract:

We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.

Natural Compound And Ovarian Cancer

Berbamine, a natural compound used in Chinese traditional medicine, has anti-tumor effects, and induced death of ovarian cancer cells by suppressing the Wnt signaling pathway.  Abstract:

Ovarian cancer is a common and lethal cancer affecting women globally. Berbamine is a natural compound from the plant Berberis amurensis, which is used in Chinese traditional medicine. Recent studies have shown the anti-tumor effects of berbamine in several types of cancers but not in ovarian cancer. In the present study, we investigated the potential anti-tumor effects of berbamine in ovarian cancer and explored the underlying molecular mechanisms. Berbamine suppressed the cell viability of ovarian cancer cells in a concentration-dependent manner as revealed by methyl thiazolyl tetrazolium assay. Berbamine also suppressed the cell growth and invasion of ovarian cancer cells as measured by colony formation and cell invasion assays, respectively. Flow cytometry experiments showed that berbamine increased cell apoptotic rate and induced cell cycle arrest at G0/G1 phase in ovarian cancer cells. Western blot analysis showed that berbamine increased the protein levels of cleaved caspase-3, cleaved caspase-9, Bax, and decreased the protein level of Bcl-2 in ovarian cancer cells. Quantitative real-time PCR and western blot analysis demonstrated that berbamine treatment inhibited the Wnt/β-catenin signaling in ovarian cancer cells. The inhibitory effects of berbamine on cell viability and invasion of ovarian cancer cells can be partially reversed by lithium chloride (LiCl) treatment. Growth of tumors developed from SKOV3 cells was significantly suppressed in berbamine-treated group, and berbamine treatment enhanced caspase-3 and -9 cleavage and reduced β-catenin protein level in tumor tissues. In summary, berbamine exerts its anti-cancer effects in vitro and in vivo via induction of apoptosis, partially associated with the inhibition of Wnt/β-catenin signaling.

Plant Compound Against Breast Cancer

A plant-derived natural compound inhibits breast cancer cell growth and metastasis by repressing Wnt signaling.  Abstract:

Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/β-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and β-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) β-catenin protein levels, but not total β-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/β-catenin signaling pathway.

Chromatin Remodeling And Cancer Immunotherapy

CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=35818927

Immunotherapy against cancer is a promising treatment approach, but resistance is a problem. It has been shown that the expression of certain chromatin remodeling factors – that alter chromatin structure to affect gene expression – are associated with immunotherapy resistance in human cancer.  Inactivating these factors increases sensitivity to treatment, perhaps by altering the expression of genes that influence response to treatment.  This is an avenue of research that has clinical implications.  Abstract:

Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

More On Combination Drug Therapy For Cancer

Combination drug therapy for cancer has been thought to always involve the drugs working together in an additive or even synergistic fashion.  However, one study shows that in some cases, the efficacy of drug combinations is solely due to patient-to-patient variability in response and the independent action of the drugs.  So, assume you have two patients, Bill and Mary, both with the same type of cancer, and they are given combination therapy with drugs A and B.  The traditional idea was that success would be due to A and B both working equally in both patients, or working synergistically; this new study suggests that in some cases, if you don’t know in advance which drug is best for what patient, you give both, and maybe Bill responds to A and Mary to B, and you see a success that you would not have seen if you had given both patients either A or B – so you get 100% success instead of 50%. Keep in mind that there are of course cases where combination therapy does wok additively or synergistically.  Abstract:

Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.

Plant Extract Against Colon Cancer?

Anti-cancer benefits of a plant extract, mediated through inhibition of Wnt signaling. This may be useful for developing preventive or therapeutic approaches to colon cancer.  Abstract:

OBJECTIVE:

To investigate the effect of the ethanol extract of Scutellaria barbata D. Don (EESB) on colorectal cancer (CRC) growth and Wnt/β-catenin signaling pathway in vivo and in vitro.

METHODS:

In vivo experiment, CRC xenograft mouse model was constructed with injection of HT-29 cells. Following xenograft implantation, twenty mice were randomly divided into EESB-treated group (n=10) and control group (n=10) by a random number table, and were given with intra-gastric administration of 2 g/kg EESB or saline, 5 days a week for 16 days, respectively. At the end of experiment, tumors were removed and weighed by electronic scales. The proliferation biomarker Ki-67 of tumor was evaluated by immunohistochemistry (IHC) assay. In vitro study, HT-29 cells were treated with 0, 0.5, 1.5, 2.5 mg/mL EESB for 24 h. At the end of the treatment, the viability and survival of HT-29 cells were determined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and colony formation assay, respectively. The mRNA expression of c-Myc, Survivin and adenomatous polyposis coli (APC) was examined by reverse transcription-polymerase chain reaction (RT-PCR) both in tumor tissues of CRC xenograft mice and HT-29 cells. Protein expression of c-Myc, Survivin, APC, and β-catenin as well as β-catenin phosphorylation level were evaluated by IHC assay or Western blotting.

RESULTS:

EESB significantly reduced tumor weight in CRC xenografts mice, compared with the control group (P<0.05). IHC assay showed that EESB significantly inhibited protein expression of Ki-67 in tumor tissues (P<0.05). MTT assay showed that EESB significantly reduced HT-29 cell viability in a dose-dependent manner (P<0.05). Colony formation assay showed that EESB dose-dependently decreased the survival of HT-29 cells (P<0.05). In addition, RT-PCR assay showed that EESB decreased the mRNA expression of c-Myc and Survivin and increased APC expression, both in tumor tissues of CRC xenograft mice and HT-29 cells (P<0.05). IHC assay or Western blotting showed that EESB decreased protein expression of β-catenin, c-Myc and Survivin, as well as increased APC expression and β-catenin phosphorylation in tumor tissues or HT-29 cells (P<0.05).

CONCLUSIONS:

EESB significantly reduced tumor growth in CRC xenografts mice, and inhibited the viability and survival of HT-29 cells. EESB could suppress the activation of the Wnt/β-catenin pathway, which might be one of the mechanisms whereby Scutellaria barbata D. Don exerts its anticancer activity.

Problems With Cancer Model Systems

Patient-derived xenografts (PDXs) – where human tumors are transplanted into immunodeficient mice to test for therapeutic approaches – are popular research models in cancer research.  The underlying premise is that the transplanted tissue will “faithfully represent” the original human tumor, but here is a paper suggesting otherwise, showing significant genetic changes that occur.  This of course puts into question how effective the model system is.  It is important to know the limitations of a model system and strive for improvement; it is also important to use the tools at hand.  There is currently no perfect model system for human cancer.  Human cancer cells in culture are a very useful model, but cells in culture are not a human tumor, and the cells of course change over time, so they are not “faithfully representing” the original tumor; various 3-D cell culture models, organoids, etc. are useful but also come with caveats; animal models (transgenics, xenografts, dietary or chemical challenges on wild-type mice) are also useful, but we remember that mice are not humans, and as we see in this paper, transplanted human tissue can change over time.  There is always a hurdle going from therapies tested in model systems to their efficacy in actual human patients, and the variability between models and humans is one major cause for this.  But we must do the best we can with the tools we currently have at hand.  With all their faults, PDXs can yield valuable data; we just need to be careful with the interpretation – and always look toward developing a better model system.  Abstract:

Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer.

Biomarkers For Metastatic Colon Cancer Treatment

Metastatic colon cancer patients would benefit from having biomarkers analyzed, to judge potential response to certain therapeutic approaches.  This makes sense, as variation in signaling pathways can affect response to treatments, particularly those that target the altered pathways or other pathways that communicate with those altered.  Abstract:

BACKGROUND:

Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways.

METHODS:

We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment.

RESULTS:

We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC.

CONCLUSIONS:

We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment. British Journal of Cancer advance online publication 12 October 2017; doi:10.1038/bjc.2017.353 www.bjcancer.com.

Bacteria And Chemotherapy Resistance

Bacteria associated with tumors can mediate resistance the chemotherapy drugs. Thus controlling bacterial species in cancer can enhance the efficacy of chemotherapy.  

There is a general pattern emerging from recent research of the importance of bacteria to human other than the simple paradigm of "there's a bacteria infection, give antibiotics." Bacteria we normally carry with us - such as the gut microbiota - affect human health for better or worse, as chronicled at this blog in a number of posts; now we see that human cancer can be associated with bacteria that affect resistance to chemotherapy.

Targeting human-cancer-bacteria interactions seems like a fruitful area of future research.

Cancer Cell Drug Addiction

By United States: National Institutes of Health - http://www.nih.gov/about/discovery/chronicdiseases/cancer.htm, Public Domain, https://commons.wikimedia.org/w/index.php?curid=25303787

Interestingly, cancer cells can not only become resistant to chemotherapeutic treatments, they can even become "addicted" to the drugs, actually becoming dependent on the drugs for growth!  In that sense, the drug are actually at that point feeding further tumor growth, and removing the drug can cause cancer cell death.  The mechanisms behind this is not well understand, and identifying these mechanisms would be helpful for designing more optimal therapeutic approaches (including alternating therapy regimens).  New data suggest certain cell signaling pathways may be involved.  Stay tuned for further developments; this is an important story.  Abstract:

Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.

TAXPAYERS MONEY WILL BE FLUSHED

Twenty years from now, you’ll be more disappointed by the things you didn’t do than the ones you did do. So throw off the bowlines. Sail away from the safe harbor. Catch the trade winds in your sails. Explore. Dream. Discover.
Mark Twain


There is not too much of “explore, dream, discover” in Obama’s initiative about cancer, the Cancer Moonshot initiative. I have already written about it. Since my last commentary, a Blue Ribbon Panel was assembled, and this distinguished panel came up with ten recommendations.

Remember my prediction, the one that the $1 billion would go directly where the other billions of dollars have gone in the past 45 years? The money will go for CANCER TREATMENT, not PREVENTION. Yes, I was right, nine out of ten recommendations designate the money for treatment.

If the listed below recommendations were anonymously reviewed by any NIH NCI peer review panel, they would have been dismissed as not well justified, low impact, and catering to profit-driven interests.

Feast your mind on the following recommendations:

A. Establish a network for direct patient involvement: …this recommendation calls for cancer patients to join a new national network that … will provide them with a genetic profile of their cancer and let them “preregister” for clinical trials.

My response: Please, re-think the clinical trials first, then ask for more patient participation. There was an excellent idea on re-structuring the current "randomized controlled" clinical trials in the documentary “Surviving terminal cancer”.



B. Create a clinical trials network devoted exclusively to immunotherapy … for pediatric and adult cancers …to advance research in this area and could lead to new vaccines to prevent cancers of all types in children and adults.

My response: Where is the high impact in this maneuver? Also, I have not seen any rationale in this approach: how exactly would a clinical trials network result in new vaccines that prevent all cancers? Was this recommendation even written by a scientist or a sci-fi writer?

 

C. Develop ways to overcome resistance to therapy… this calls for establishment of multidisciplinary research teams to understand how drug resistance develops and find ways to prevent tumors from resisting the drugs meant to kill them.

My response: Really, the molecular mechanisms of drug resistance are extremely well studied. It is a matter of implementing the accumulated knowledge.

 
D. Build a national cancer data ecosystem… this would link many of the nation’s largest data repositories to enable one-stop, free access for researchers, doctors, and patients to share data on cancer and fuel faster progress.

My response: I am always suspicious when someone uses unusual combinations of words such as “national cancer data ecosystem”. Try to put it simply, for example: “implement obligatory sharing of data”. This is good, but how are we going to achieve it?
 


E. Intensify research on the major drivers of childhood cancers … intensifying research in cell biology, genomics, proteomics, and drug development would accelerate development of new therapies that target these cancer-causing proteins.

My response: Of course, we need to continue researching childhood cancers. I am not sure how this constitutes a novel and breakthrough recommendation? I assume we have been doing it all along.


F. Minimize cancer treatment’s debilitating side effects …this should support development of guidelines for managing patient-reported symptoms and side effects of cancer treatment in adults and children, with the goal of helping patients stay on their drug regimens and improve their quality of life.

My response: How about managing the health awareness and lifestyle factors that predispose to cancer instead? “Helping patients stay on their drug regimen”? Does this sound like trying to increase the profit for big pharma?



G. Expand use of proven prevention and early detection strategies…several cancer prevention and risk-reduction strategies have proven to be effective, including tobacco control, colorectal cancer screening, and HPV vaccination. The recommendation also calls for increasing testing for hereditary cancer syndromes in people with certain types of cancer and their family members, so those identified as high risk can begin early prevention or screening efforts.

My response: Out of the ten recommendations, this is THE ONLY one that deals with prevention, and YET, it does not mention the major lifestyle factors that contribute to cancer today: our sugar-laced diet, the physical inactivity, and the obesity. Tobacco use has been decreasing in the U.S. and we should continue doing whatever we have been doing about it.

Of course, the profit had to be factored even in a "prevention" recommendation: why not start excessively sequencing and screening, if someone could profit from it? Remember, the hereditary cancer syndromes account for maximum 20% of all cancers. The other 80% are mostly due to lifestyle, environment, age. Behavioral changes and educational efforts are implemental; however, they are not even mentioned here.


H. Mine past patient data to predict future patient outcomes: … we need to understand why patients with the same type and stage of cancer, and same treatment end up with different outcomes. The idea is that analyzing the tumor tissue from patients may discover genetic and other factors that impact response.

My response: We already know that amazingly diverse factors modulate the treatment response of individual patients. Instead, we should focus on the main factors/approaches that we know impact almost ALL cancer patients. How about examining the effect of ketogenic dietary regimens that could benefit more than 90% of all cancer patients? Or how about researching Coley's vaccine and why 40-50% of the advanced cancers were cured with this approach?


I. Develop a 3D cancer atlas: a web-based catalog of the genetic lesions and cellular interactions in tumor, immune, and other cells in the tumor microenvironment. The hope is that we will learn about the “evolution of tumors” and this will allow for developing predictive models of tumor progression and response to treatment.

My response: This is equivalent to going fishing into a land without any water body, not even a puddle. We already know that there is not only inter-individual heterogeneity of primary cancers, but also heterogeneity between the cells in the primary cancer in a patient, heterogeneity within the cells of a single metastasis, and between the cells of different metastases of the same individual. Why do we think that we can make sense of the cancer cell "insanity"? This expedition is hopeless. Instead, focus on the initial stages of neoplastic development, when we can really have an impact.
 

J. Develop new cancer technologies: increase the public–private sector collaboration to develop new tools or refine technologies (e.g., implantable microdosing devices that deliver drugs directly into a tumor to test their effectiveness, and advanced imaging technologies to study cancers at extremely high resolution).

My response: These new high-tech toys may not have any impact since the drugs used for the treatment would be the same. The only result will be the escalation of the cancer care cost.

"Divide and conquer" - does it work in cancer care

Fotogeniss -

Philip-ii-of-macedon

"Divide and conquer" may have worked for Philip II of Macedon; however, is it an effective strategy in understanding cancer development and providing cancer care?    

Have you seen the talk by Dr. Gary Fettke, "Nutrition and Cancer - Time to Rethink"? The talk leads to the conclusion that cancer is a disease of our metabolism. The chromosomal changes, including any gene mutations, seem to be bystanders in the unfolding madness of cancer development.

However, recent research indicates that all cancer cell changes (mutations and metabolic changes), the immediate environment of the cancer cells (influenced by external environmental and internal factors), and the metabolism at the organism level are interconnected, and contribute to the neoplastic growth.

It is not any single element, it is rather the congregation of factors that allows for the abnormality of cancer to emerge, persist, and eventually kill.

We should be mindful of the perils of reductionism in science and cancer prevention/treatment, and try to adopt a holistic view on cancer. Here are the precise definitions of the two approaches:

Reductionism,
the practice of analyzing and describing a complex phenomenon in terms of simpler, more fundamental phenomena...

versus...

Holism,
the theory that parts of a whole are in intimate interconnection, such that they cannot exist independently of the whole, or cannot be understood without reference to the whole...

For more examples on misleading reductionism see here.



ACTIONABLES:
Yes, we should be aware of not only what we eat but how we eat it.

Yes, we should stop drinking to death, and I am not even referring to drinking alcohol.

Yes, we should learn how to cook for ourselves, since the food industry is force-feeding us with loads of sugar.

Yes, you should educate yourself, and not rely on your doctors and mainstream media to do so.

Yes, all of us should be aware that it is easier to deal with a just-born, immature troublemaker than a fully established, mature enemy; in other words, cancer prevention is more effective than cancer treatment.

Yes, we should try to integrate mainstream and alternative approaches to cancer care.

And yes, for all of you cancer researchers and enthusiasts: analyzing a phenomenon by breaking it down to its elements/building blocks and addressing only a single element is not going to bring a success. Cancer prevention and treatment need to address all aspects of the cancer development.

Pointing fingers does not work – in everyday life or in cancer treatment

We all know how the ritual of pointing fingers starts after a somewhat-preventable disaster strikes. However, identifying the culprits does not reverse the disaster.

In the past 20 years or so, “pointing fingers” has also been our major strategy against cancer. The prevalent notion is that we can deal with cancer by pointing out at the mutations that contribute to abnormal cell development. The eureka moment goes like this “AH, IT IS THE MUTATION IN THE GENES X, Y, and/or Z that causes cancer.” This realization is followed by the design of a compound against the mutant X, Y or Z products. Does it work? To be fair, the strategy works sometimes. In most cases, however, the strategy yields return only for the drug company. Why?

1. The approach is this of management of the disease, but not cure of the disease (usually).

2. Each cancer patient has a unique combination of gene mutations causing cancer.

3. With time, each cancer changes its mutation profile (this is known as the "evolution" of cancer). If at the beginning of the treatment the mutations are X, Y, and Z, by the end of the treatment there could be newly identified mutations Z, W, and D. The outcome? The patient dies, the pharmaceutical company profits, and the patient’s family might be financially broke.

What is wrong with this picture? 

Everything!

Before any disaster strikes and before we reach the stage of pointing fingers, there is a period, when the potential for a disaster could be evaluated and if high, could be addressed.

Cancer is not different from other disasters. There are risk factors we can eliminate and signals that we can detect BEFORE CANCER STRIKES.

P.S. As I was writing this post, it was confirmed that in the next 4 years $240 million tax payers money will be spent on sequencing 200,000 human genomes. The goal is to identify genes that modulate our risk of diabetes, heart disease, and autism.  I am still waiting to hear about an anti-obesity program funded as generously as this sequencing project. Perhaps, decreasing obesity makes no sense, since we already know that obesity is the major cause of all rampant chronic conditions in this country, including heart disease, diabetes, and cancer?

Worth watching

I recently watched the documentary Surviving Terminal Cancer. It was painful and sad.

As a cancer researcher I can testify that any treatment not approved by FDA in the U.S. is "anathema" among the researchers - it is extremely rare that one can obtain funding to (a) develop and study anything other than drugs churned out by big pharma, or (b) make microscopic advancements within the officially approved fads in cancer research. If one makes a mistake to go beyond these boundaries and proposes to do research that does not fit the mainstream science, s/he is never funded and abundantly ridiculed and chastised by the National Institutes of Health reviewers of grant proposals. Considering that cancer research requires huge funds, it is obvious that non-conformists would never be funded and their ideas would meet a dead end.

In clinic, in order to keep their licenses and reputations, the oncologists simply have no choice, but to obey the system and offer the cancer patients the three pillars of conventional therapy (i.e., radiation, chemotherapy, surgery).

What is the solution? It is spelled out in the movie - watch it and find out. The documentary is a must-see for everyone: for health care providers, researchers, patients, and in general, for everyone who wants to know how we design and structure cancer care today and how we could do better in the future.

This documentary delivers a very different message from the mainstream media - approved and pharmaceutical company - funded PBS documentary The Emperor of All Maladies. Surviving Terminal Cancer, above all, it delivers an ACTIONABLE message.  

Thank you to the creators of the movie and the participants!