Dr. Qun LuLeo Jenkins Cancer Center at BSOM
UNC Lineberger Comprehensive Cancer Center
Contextual Contributions of Oncogenic and Tumor Suppressive Pathways:
- Our Opportunities and Challenges in Therapeutic Development -
Our Progresses in The Past Four DecadesOur Progresses in The Past Four Decades
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Target specific drugs such as Gleevec and Iressa By specifically blocking the abnormal protein called BCR-ABL, Gleevec kills the
leukemia cells. By inhibiting tyrosine kinase activity of EGFR, Iressa suppresses NSCLC.
Remarkable Treatment SuccessesRemarkable Treatment Successes Cytotoxic chemotherapy drugs such as Cisplatin
Before cisplatin was available, metastatic testicular cancer had a mortality rate of 95%. Cisplatin based regimens resulted in a 60% cure rate for this disease.
What are the modern What are the modern strategies for drug discovery strategies for drug discovery against cancer?against cancer?
Most strategies for cancer drug discovery focus on attacking specific elements of a given biological pathway of cancer cells to achieve target specificity with minimized toxicity. This approach, although with long term merits, has not produced the desired numbers of viable drugs because most such leads succeeded in vitro or in animal studies do not show the same efficacy in human trials. Consequently, few viable cancer drugs enter markets in recent years leading to skyrocketed R&D cost.
Billions of dollars have been invested on R&D, why are Billions of dollars have been invested on R&D, why are we still so far away from conquering cancer?we still so far away from conquering cancer?
(2009) (2010) (2010)
Dichotomy of Oncogenes and Tumor Suppressors Challenges Anti-cancer Therapies
Surprising Discoveries in Cancer ResearchSurprising Discoveries in Cancer Research
Oncogenic Versus Tumor Suppressive Signaling PathwaysWhen oncogenes were identified, we thought that we have
found the bad guys. So the theory was that if we inhibit the functions of oncogenes, we can stop the disease. It was also thought that since there are tumor suppressors, we can increase the function of the tumor suppressors to inhibit the disease progression.
However: Many genes and many signaling pathways can be oncogenic in one context, but be tumor suppressive at a different context or at different stages.
Myc-pRb-E2F axisMyc-pRb-E2F axis
Myc oncogene expression is deregulated in 15 to 30 % of human cancers, resulting in elevated levels of Myc protein.
As mitogenic promoter: Myc perturbs the decision to phosphorylate tumor suppressor pRb and thereby alter cell cycle progression.
As pro-apoptotic factor: Myc induces cell to undergo apoptosis unless they have been protected from apoptosis by some other, previously acquired anti-apoptotic allele (e.g., a ras oncogene).
In the presence of the anti-apoptotic mutation, the strong mitogenic effects of the myc oncogene then become apparent.
As proliferation promoter: both Myc and Ras can activate E2F transcription factor, which can initiate cell proliferation.
As pro-apoptotic factor: both Myc and Ras can also activate E2F transcription factor, which can initiate cell death.
Indeed, the oncogenic roles of E2F could be context-dependent.
Zhang et al., 2010. Future Oncology
TGF TGF 1 signaling axis1 signaling axis As a tumor suppressor: for most normal epithelial cells and at the early stages of tumor development. This process occurs largely through the activation of TGF 1 receptor complex and phosphorylation of Smads and other signaling pathways.
As metastasis promoter: elevated expression of TGF 1 may enhance malignant properties of tumor cells through effects on cell invasion, metastasis, epithelial to mesenchymal transition (EMT), or anti-tumor immunity. This alteration in functions of TGF 1 in cancer development is likely due to its interaction with other signaling pathways such as ras oncogene that becomes activated during tumor progression.
Phosphatidylinositol 3-kinases (PI3Ks) signaling axisPhosphatidylinositol 3-kinases (PI3Ks) signaling axis
Oncogenic functions of PI3K: In cell-based assays, PIK3CA mutations confer a gain of function as measured by lipid kinase activity, constitutive activation of Akt, and cellular transformation. Therefore, the frequency of PIK3CA mutation is consistent with the significance of PI3Ks in breast cancer pathogenesis.
Positive prognostic significance of PIK3CA mutations: Some studies indicate that PIK3CA can even be a “good” activating mutation in cancer. This is clinically relevant, because it could significantly affect the design of clinical trials planned for PI3K-targeted therapy.
Zhang et al., 2010. Future Oncology
-Catenin
p120-catenin
p0071
ARVCF
-Catenin
β-Catenin
Armadillo 843 aa
781 aa
745 aa
968 aa
962 aa
1211 aa
1225 aa
-Catenin in comparison to other armadillo domain containing proteins
The Armadillo/β-catenin superfamily
DSWV
Incompatible Observations Incompatible Observations on Human tissues and Cultured Cell Lineson Human tissues and Cultured Cell Lines
- Make drug discovery more challenging- Make drug discovery more challenging
Esophagus食管
Benign
CancerBreast乳腺
Prostate前列腺
Lung
Lu et al., 2005(180 cases TMA)
Zhang et al., 2010135 cases NSCLC
Promoter Mutations Can Increase Promoter Mutations Can Increase -Catenin-Catenin ExpressionExpressionin Prostate Cancer (PCa) Cellsin Prostate Cancer (PCa) Cells
Wang et al., 2009. Oncogene
In Culture, In Culture, -Catenin Expression Is Moderate -Catenin Expression Is Moderate But Its Expression Increases PCa Cell Viability But Its Expression Increases PCa Cell Viability
and Tumor Xenograft Growth and Tumor Xenograft Growth
Zeng et al., 2009. Mole Cancer
MDCK Cells
However, However, -Catenin Also Displays Tumor Suppressive Activities -Catenin Also Displays Tumor Suppressive Activities
Lu et al., 1999; J. Cell Biol Westbrook et al., 2005; Cell
HMEC Cells
PCa Cells
Zeng and Lu, unpublished
So, Why Does So, Why Does -Catenin Display Opposite Functions ? -Catenin Display Opposite Functions ? Does Its Mutations Play a Role in PCa Cell Fate and Behavior? Does Its Mutations Play a Role in PCa Cell Fate and Behavior?
-Identification of -Identification of -Catenin Mutations in Cancer--Catenin Mutations in Cancer-
Nopparat and Zhang et al., 2015. Oncogene
-Catenin 1225 aa
Identification of Functional Identification of Functional -Catenin Mutations -Catenin Mutations in Human Prostate Cancerin Human Prostate Cancer
1027. 1095, 1096 1142
811, 816
Mutations occur at Mutations occur at very high frequency;very high frequency;
Mutations occur in Mutations occur in other cancer types as other cancer types as well;well;
May affect May affect -catenin -catenin functions.functions.
Patent pending
Ovary cancer: P1218L(Primary tumor)
Large intestine: Y1128fs*6(Culture sample)Large intestine: P1159S(Culture sample)
NSCLC: K703R(Culture sample)
Pancreas cancer: A685V(Culture sample)
Skin cancer: F1172F(Culture sample)
Majority of Cancer Associated Mutations Are Limited Majority of Cancer Associated Mutations Are Limited to the Carboxyl Half of to the Carboxyl Half of -Catenin-Catenin
Prostate cancer: K811N, K811Q, K1027Q, S1095S(Primary tumor)
Prostate cancer: K816R, N1096R, S1140QBetween exon 21 and 22—EGFR(Primary tumor)
No-sense or Missense Mutations:No-sense or Missense Mutations:
Deletion or insertion:Deletion or insertion:
Lu et al., 1999
Zhang and Lu, unpublished
Mutations Can Alter Mutations Can Alter -Catenin-Catenin Localization in Localization in CellsCells
811, 816
Differential Differential -Catenin-Catenin Localization May be Driven Localization May be Driven by Mutations in Prostatic Tumorsby Mutations in Prostatic Tumors
Some Some -Catenin Mutations May Lead to Gain-of--Catenin Mutations May Lead to Gain-of-Functions in Cell Proliferation/Survival, Functions in Cell Proliferation/Survival,
Adhesion, and Energy MetabolismAdhesion, and Energy Metabolism
Compound Transgenic Mice Expressing Both Oncogenic Myc and δ-Catenin Mutation
AcknowledgemenAcknowledgementsts
The Lu LabThe Lu Lab• Amy FrieslandAmy Friesland• Joyce ZhangJoyce Zhang• Christi BoykinChristi Boykin• Jian-Ping LuJian-Ping Lu• Tao WangTao Wang• Yan ZengYan Zeng• Kwonseop KimKwonseop Kim• Sarah JamesSarah James• Sonja Bareiss Sonja Bareiss
CollaboratorsCollaborators• Yan-hua ChenYan-hua Chen
• Lei DingLei Ding
• Huchen ZhouHuchen Zhou
• Robert MatusikRobert Matusik
• Scott ShappellScott Shappell
• Frank LongoFrank Longo
• Baoan ChenBaoan Chen
• Xuemei WangXuemei Wang
Contextual Contributions of Oncogenic and Tumor Suppressive Pathways
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