Cancer Research in 2019: Dazzling Opportunities, Daunting Challenges - - PowerPoint PPT Presentation

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Jun 15, 2023 44 likes •194 views

Cancer Research in 2019: Dazzling Opportunities, Daunting Challenges M. Celeste Simon, Ph.D. Women in Oncology November 11, 2019 Limited O 2 Availability in Solid Tumors Hypoxia Inducible Factor Pathways Simon, MC (2016) New Engl. J. Med.

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Cancer Research in 2019: Dazzling Opportunities, Daunting Challenges

M. Celeste Simon, Ph.D.

Women in Oncology November 11, 2019

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Limited O2 Availability in Solid Tumors

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Hypoxia Inducible Factor Pathways

Simon, MC (2016) New Engl. J. Med. 375:1687

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Source: The Nobel Prize

Bill Kaelin, Peter Ratcliffe, Gregg Semenza win 2019 Nobel Prize!!!

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1) ES cell gene targeting at Harvard (1988-1992). 2) ES cell in vitro differentiation (1988-1990). 3) Nothing worked for two years. 4) Almost quit……

“Perseverance when the going gets tough!!!”

Simon, MC (2018) Nat. Cell Biol. 20:1008

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O2 gradients in embryos and tumors

E9.5 E8.5 O2

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Arnt+/+ Arnt -/-

Abnormal angiogenesis in HIF-deficient embryos

Maltepe E et al. (1997) Nature 886:403

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EF5 - hypoxic

Oxygen diffusion limited in solid tissues…

Oxygenated PECAM (CD31)

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Metabolic Pathways Active in Proliferating Cells

Lunt, SY and MG Vander Heiden (2011) Annu. Rev. Cell Dev. Biol. 27:441

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Question: Do disparate oncogenic changes converge on more common metabolic adaptations?

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Clear Cell Renal Cell Carcinoma (ccRCC)

5 yr. survival
>85% if highly localized
<10% if metastatic
Resistant to conventional chemo- and radiotherapy
Hallmarks of disease:
Constitutive HIF activity
100X cholesterol esters, 8X cholesterol, 20X triglycerides*

*Qiu, B et al. (2015) Cancer Disc. 5:652

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Metabolic profiling of ccRCC tumor and normal kidney

Urea cycle; arginine and proline metabolism Nicotinamide (NAD) and Riboflavin (FAD) metabolism Carnitine metabolism Long chain fatty acid Lysolipids

Li, B et al. (2014) Nature 513:251 Hakimi, A et al. (2016) Cancer Cell 29:104

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Glucose Glucose 6-phosphate Glycolysis Gluconeogenesis HK2 Fructose 6-phosphate PFK1 FBP1 Fructose 1, 6-bisphosphate Phosphoenolpyruvate PKM2 Pyruvate Lactate TCA cycle LDHA FBP1 HIFs

GLUT1 ENO1 PKM2 LDHA

x

PFK1 TEAD YAP/ TAZ

Target expression

HIF-1α PKM2

PDK1 GLUT1 LDHA VEGF

JMJD5 PHD3 P300/ CBP Nucleus Nucleus Nucleus

Metabolic Enzymes in Strange Places!!

Huangyang, P and MC Simon (2018) Dis. Mod. Mech. 11:18 Huangyang, P et al. (2019) Cell Metab., in press

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Dazzling Opportunities:

1. Technology advancement. 2. Translational impact. 3. Global collaboration. 4. How “cancer” biology reveals fundamental insights into “normal” biology.

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Daunting Challenges:

1. Longer “time to degree” time spans (especially MD/PhD and Vet/PhD students). 2. Longer postdoctoral fellowships. 3. Exceptionally long training periods for physician- scientists. 4. 2019 definition of a “publication unit”. 5. NCI FY2020 7% payline (Can this be possible??). 6. Pressure point: tenure track assistant professors. 7. Pressure point: first R01, K08 for clinical fellows.