Tumor cell heterogeneity and resistance; report from the 2018 Coffey‐Holden Prostate Cancer Academy Meeting

Miyahira, Andrea K.; Den, Robert B.; Carlo, Maria I.; Leeuw, Renée de; Hope, Thomas A.; Karzai, Fatima; McKay, Rana R.; Salami, Simpa S.; Simons, Jonathan W.; Pienta, Kenneth J.; Soule, Howard R.

doi:10.1002/pros.23729

Cited by 15 publications

(11 citation statements)

References 142 publications

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“…There is an emerging appreciation for the effect of epigenetic changes through DNA methylation, chromatin remodeling, and histone/protein methylation, which results in functional changes in tumor cells 202 . Collectively, these events contribute to tumor cells (and sometimes foci of tumor cells) with altered and diverse functions, which impose challenges if only genome and transcript biomarkers are being factored into clinical decision making 203 …”

Section: Tumor Heterogeneity Cellular Plasticity and Drug Resistancementioning

confidence: 99%

Blueprint for cancer research: Critical gaps and opportunities

Elmore

Greer

Daniels

et al. 2020

CA A Cancer J Clinicians

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We are experiencing a revolution in cancer. Advances in screening, targeted and immune therapies, big data, computational methodologies, and significant new knowledge of cancer biology are transforming the ways in which we prevent, detect, diagnose, treat, and survive cancer. These advances are enabling durable progress in the goal to achieve personalized cancer care. Despite these gains, more work is needed to develop better tools and strategies to limit cancer as a major health concern. One persistent gap is the inconsistent coordination among researchers and caregivers to implement evidence‐based programs that rely on a fuller understanding of the molecular, cellular, and systems biology mechanisms underpinning different types of cancer. Here, the authors integrate conversations with over 90 leading cancer experts to highlight current challenges, encourage a robust and diverse national research portfolio, and capture timely opportunities to advance evidence‐based approaches for all patients with cancer and for all communities.

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Section: Tumor Heterogeneity Cellular Plasticity and Drug Resistancementioning

confidence: 99%

Blueprint for cancer research: Critical gaps and opportunities

Elmore

Greer

Daniels

et al. 2020

CA A Cancer J Clinicians

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“…The opposite is also true that in a cancer mass some cells' ability of self-renewal via symmetrical division is much more potent than that of the others. However, these quantitative differences simply reflect the well-known heterogeneity of malignant cells [453,[836][837][838][839][840], which is largely ascribed to the stemness of some cells [841] and the great genetic variation among most cells [835,842], and should not be used to split cancer cells into CSC and non-CSC groups either. More critically, "ability of self-renewal vs inability of self-renewal" is actually "immortality vs mortality", which is a black-and-white demarcation between the neoplastic and non-neoplastic states and thus should not be used again as the demarcation between CSCs and non-CSCs.…”

Section: Neglecting Immortality Causes Confusion On Cancer Stem Cellsmentioning

confidence: 99%

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Dou¹,

Tong²,

Huang³

et al. 2020

J. Cancer

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Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

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“…Treatment resistance to current therapies such as antiandrogens is a persistent problem in managing prostate cancer in the clinic . Moreover, prostate cancers present with multiple genetic abnormalities and subclasses of disease .…”

Section: Resultsmentioning

confidence: 99%

“…Treatment resistance to current therapies such as antiandrogens is a persistent problem in managing prostate cancer in the clinic. 42,43 Moreover, prostate cancers present with multiple genetic abnormalities and subclasses of disease. 44 In metastatic disease, patients present with a remarkable variability of the genetic composition of the individual metastases presenting a major therapeutic challenge for adequate targeting.…”

Section: Discussionmentioning

confidence: 99%

Effective targeting of RNA polymerase I in treatment‐resistant prostate cancer

et al. 2019

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Background Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate‐limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first‐in‐class Pol I inhibitor, BMH‐21, that targets cancer cells of multiple origins, and holds potential for clinical translation. Methods The effect of BMH‐21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models. Results We show that BMH‐21 inhibits Pol I transcription in metastatic, castration‐resistant, and enzalutamide treatment‐resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH‐21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide‐resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on‐target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13‐MYC|Hoxb13‐Cre|Ptenfl/fl (BMPC) mouse prostate cancer model. Conclusion Taken together, BMH‐21 is a novel promising molecule for the treatment of castration‐resistant prostate cancer.

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Tumor cell heterogeneity and resistance; report from the 2018 Coffey‐Holden Prostate Cancer Academy Meeting

Cited by 15 publications

References 142 publications

Blueprint for cancer research: Critical gaps and opportunities

Blueprint for cancer research: Critical gaps and opportunities

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Effective targeting of RNA polymerase I in treatment‐resistant prostate cancer

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